evidence-based recommendations for short- and long-term

Can J Gastroenterol Vol 19 No 5 May 2005 285

Evidence-based recommendations for short- andlong-term management of uninvestigated dyspepsia

in primary care: An update of the CanadianDyspepsia Working Group (CanDys) clinical

management tool

Sander JO Veldhuyzen van Zanten MD1, Marc Bradette MD2, Naoki Chiba MD3, David Armstrong MD4,

Alan Barkun MD5, Nigel Flook MD6, Alan Thomson MD7, Ford Bursey MD8,

for the Canadian Dyspepsia Working Group

1Department of Medicine, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia; 2Department of Medicine,Université Laval, and the Department of Gastroenterology, Centre hospitalier universitaire de Québec, Pavillon Hôtel-Dieu de Québec,Quebec, Quebec; 3Division of Gastroenterology, McMaster University, Hamilton, and the Surrey Gl Clinic/Research, Guelph, Ontario;4Department of Medicine, McMaster University, and the Division of Gastroenterology, Hamilton Health Sciences Corporation, McMaster Site,Hamilton, Ontario; 5Department of Medicine, McGill University, and the Division of Gastroenterology, McGill University Health Centre,Montreal, Quebec; 6Department of Family Medicine, University of Alberta, and the Misericordia Community Health Centre; 7Department ofMedicine, University of Alberta, Edmonton, Alberta; and 8Health Sciences Centre, Department of Medicine, Memorial University ofNewfoundland, St John’s, Newfoundland

Correspondence: Dr Sander Veldhuyzen van Zanten, Division of Gastroenterology, Dalhousie Medical School, Queen Elizabeth II Health SciencesCentre, 1278 Tower Road, Room 928 Victoria Building, Halifax, Nova Scotia B3H 2Y9. Telephone 902-473-1499, fax 902-473-5548, e-mail [email protected]

Received for publication September 9, 2004. Accepted February 2, 2005

SJO Veldhuyzen van Zanten, M Bradette, N Chiba, et al; for

the Canadian Dyspepsia Working Group. Evidence-based

recommendations for short- and long-term management of

uninvestigated dyspepsia in primary care: An update of the

Canadian Dyspepsia Working Group (CanDys) clinical

management tool. Can J Gastroenterol 2005;19(5):285-303.

The present paper is an update to and extension of the previous sys-

tematic review on the primary care management of patients with

uninvestigated dyspepsia (UD). The original publication of the clin-

ical management tool focused on the initial four- to eight-week

assessment of UD. This update is based on new data from systematic

reviews and clinical trials relevant to UD.

There is now direct clinical evidence supporting a test-and-treat

approach in patients with nondominant heartburn dyspepsia symp-

toms, and head-to-head comparisons show that use of a proton pump

inhibitor is superior to the use of H2-receptor antagonists (H2RAs) in

the initial treatment of Helicobacter pylori-negative dyspepsia

patients. Cisapride is no longer available as a treatment option and

evidence for other prokinetic agents is lacking. In patients with long-

standing heartburn-dominant (ie, gastroesophageal reflux disease)

and nonheartburn-dominant dyspepsia, a once-in-a-lifetime

endoscopy is recommended. Endoscopy should also be considered in

patients with new-onset dyspepsia that develops after the age of 50 years.

Conventional nonsteroidal anti-inflammatory drugs, acetylsalicylic

acid and cyclooxygenase-2-selective inhibitors can all cause dyspepsia.

If their use cannot be discontinued, cotherapy with either a proton

pump inhibitor, misoprostol or high-dose H2RAs is recommended,

although the evidence is based on ulcer data and not dyspepsia data.

In patients with nonheartburn-dominant dyspepsia, noninvasive

testing for H pylori should be performed and treatment given if posi-

tive. When starting nonsteroidal anti-inflammatory drugs for a pro-

longed course, testing and treatment with H2RAs are advised if

patients have a history of previous ulcers or ulcer bleeding.

Key Words: Acetylsalicylic acid; Aspirin; Dyspepsia;

Gastroesophageal reflux disease; NSAIDs; Systematic review

Recommandations fondées sur des preuvespour la prise en charge à long et à court termede la dyspepsie non investiguée en médecinede premier recours : Le point sur l’outil deprise en charge clinique du groupe CanDys

Le présent article constitue une mise à jour et une annexe de la revue sys-

tématique précédente sur la prise en charge des patients souffrant de dys-

pepsie non investiguée (DNI) en médecine de premier recours. La

diffusion initiale de cet outil de prise en charge clinique insistait sur une

évaluation de la DNI échelonnée sur quatre à huit semaines. Cette mise à

jour se fonde sur des données récentes issues d’analyses systématiques et

d’essais cliniques pertinents.

On dispose désormais de preuves cliniques directes à l’appui de l’approche

« tester/traiter » chez les patients qui manifestent des symptômes de dys-

pepsie non dominés par les brûlures d’estomac, et des comparaisons

directes montrent que les inhibiteurs de la pompe à protons donnent de

meilleurs résultats que les anti-H2 dans le traitement initial des patients

souffrant de dyspepsie Helicobacter pylori-négative. Le cisapride ne fait plus

SPECIAL ARTICLE

©2005 Pulsus Group Inc. All rights reserved

vanzanten_8678.qxd 4/22/2005 3:01 PM Page 285

The Canadian Dyspepsia Working Group (CanDys) has pre-viously reported the development of an evidence-based

clinical management tool (CMT) for patients who presentwith uninvestigated dyspepsia (UD) to the primary care physi-cian (1). The CMT consists of five steps (Figure 1). For threeof the steps, treatment recommendations provide the physi-cian with treatment options listed according to strength of thepublished evidence, with the most effective treatment listedfirst.

The CMT uses a definition of dyspepsia that includes heart-burn and acid regurgitation symptoms that primary care physi-cians consider part of the dyspepsia symptom complex (1).This is in contrast to the Rome II Consensus Working Party,which considers heartburn and regurgitation to be diagnosticof gastroesophageal reflux disease (GERD) and distinct fromdyspepsia (2). There is more recent support for the CanDysdefinition of dyspepsia. In two studies (3,4) of Helicobacterpylori-positive patients with UD that included the symptom ofheartburn, eradication of H pylori resulted in improvement ofthe epigastric pain and in the severity of heartburn. In a largeDanish population-based dyspepsia study (5) where patientswith reflux symptoms were included, heartburn improved inpatients who were successfully treated for their H pylori infec-tion. Other data (1,6,7) have confirmed an overlap among dys-pepsia and GERD symptoms as defined by Rome II.

The present paper is an extension of the previous work bythe CanDys group (1). There are several reasons why anupdate is necessary. The initial publication of the CMT dealtonly with the initial (acute) four- to eight-week managementperiod for UD patients. There is a need for evidence-based rec-ommendations on long-term management. Second, there arenew data from primary care-based clinical studies thatstrengthen the treatment recommendations of the CMT.Finally, certain management questions were not covered in theoriginal CMT, such as once-in-a-lifetime endoscopy inpatients with heartburn because of concern about Barrett’sesophagus (BE), the role of H pylori in GERD, the use of over-the-counter (OTC) medications, and special situations such asthe management of dyspepsia in pregnancy.

METHODSThe process for the current update was the same as that used for

the generation of the original CMT. CanDys is a multidisciplinary

group consisting of academic and community-based family physi-

cians, gastroenterologists and pharmacists. A list of relevant topics

was generated and reviewed in detail. For each topic, searches

were carried out to identify new clinical trials, systematic reviews

(meta-analyses) and/or practice guidelines. All identified articles

for each particular topic were retrieved and reviewed by individual

members. The subsequent findings were presented to CanDys and

extensively discussed, including an assessment of the quality of the

evidence. Most searches were initiated broadly (ie, BE and review)

and, depending on the question, searches were refined further

(ie, risk, adenocarcinoma or treatment). Treatment or manage-

ment strategy searches focused on identification of new random-

ized controlled trials, clinical trials or cohort studies. Searches

were comprehensive; group members reviewed a large number of

citations. Potentially relevant articles were retrieved and checked

for further relevant references. Based on these searches and discus-

sions, statements were generated as to which, depending on the

topic, was a diagnostic or treatment recommendation, and these

were subsequently categorized by the group. Finally, the group voted

on all statements. This grading process has been previously

described in detail (Table 1) (1,8).

PATIENT REFERRAL MANAGEMENT ISSUESEvidence for an age cut-off of 50 years to recommendendoscopyThe recommendation for endoscopy in patients over 50 yearsof age with chronic, stable symptoms stems mainly from expertopinion expressed in practice guidelines. In considering therole of endoscopy, it is important to determine what the find-ings would be if endoscopy were performed in all patients andwhether this would alter management. In the Canadian AdultDyspepsia Empiric Treatment – Prompt Endoscopy (CADET-PE)study (6), 1040 patients with UD underwent prompt endoscopywithin seven to 10 days, without therapy, after presentation totheir family physician. The study was designed to provide dataon the prevalence of clinically significant endoscopic findingsin undifferentiated UD patients. The majority (58%) of UDpatients did have clinically significant findings at endoscopy.Esophagitis was by far the most common diagnosis (43%),while duodenal and gastric ulcers were found in 2.8% and 3%,respectively. Esophagitis was more common (55%) in patientswith dominant symptoms of heartburn or acid regurgitation.More important, endoscopic esophagitis was seen in 36% ofpatients who did not have dominant heartburn or acid regurgi-tation. The majority of patients with gastric (55%) and duo-denal ulcers (69%) were H pylori-positive. Because symptomsare not good predictors of the endoscopic findings, these datasupport the significant overlap that exists between dyspepsiaand GERD, and argue against the Rome II statement thatGERD symptoms define the disease. Finally, the results indi-cate that endoscopy is unlikely to change medical manage-ment and, therefore, it is reasonable to proceed with anempiric trial of therapy as defined in the CMT.

In the CMT, endoscopy is recommended for patients overthe age of 50 years who present with new-onset dyspepsia. Thisrecommendation remains unchanged although this age cut-offis largely based on the incidence of gastric and esophageal can-cer, which starts to increase significantly over 50 years of age,albeit slowly. Recent data (9-21) confirm that mostesophageal and gastric malignancies present with alarm fea-tures and, thus, further support that the presence of any alarm

Veldhuyzen van Zanten et al

Can J Gastroenterol Vol 19 No 5 May 2005286

partie des options thérapeutiques offertes et les preuves relatives aux

autres agents procinétiques sont lacunaires. Chez les patients qui souf-

frent d’une dyspepsie de longue date, dominée par la présence de brûlures

d’estomac (c.-à-d., RGO) ou non, une endoscopie unique est recom-

mandée. L’endoscopie devrait aussi être envisagée chez les patients dont

les premiers signes de dyspepsie se manifestent avant l’âge de 50 ans. Les

AINS classiques, l’acide acétylsalicylique et les inhibiteurs sélectifs de la

COX-2 peuvent tous causer la dyspepsie. S’il est impossible d’en cesser

l’usage, on recommande leur coadministration avec un inhibiteur de la

pompe à protons, du misoprostol ou un anti-H2 à forte dose, bien que les

preuves reposent sur des données issues d’études sur les ulcères plutôt que

sur la dyspepsie. Chez les patients dont la dyspepsie ne se manifeste pas

principalement par des brûlures d’estomac, il faut procéder à un dépistage

non effractif de H. pylori et instaurer le traitement approprié selon les

résultats. Lorsqu’on commence un traitement prolongé au moyen

d’AINS, il est recommandé de procéder à des tests et de traiter au moyen

d’anti-H2 si les patients ont des antécédents d’ulcères ou d’hémorragies

digestives.

vanzanten_8678.qxd 4/22/2005 3:01 PM 86

feature (vomiting, bleeding/anemia, abdominal mass, unex-plained weight loss, dysphagia) is an indication for endoscopy.There are no randomized controlled data to support or refutean age cut-off of 50 years and, therefore, this arbitrary assign-ment remains based on expert opinion. The AmericanGastroenterology Association, American College ofGastroenterology, British Society of Gastroenterology andEuropean Society of Primary Care Gastroenterology recom-mend endoscopy over the age of 45 years (9-12). The 1998Dyspepsia Working Party report from the World Congresses ofGastroenterology (13) suggests an age cut-off of 50 years inWestern nations. The updated British Society ofGastroenterology guidelines (14) suggest an age of 55 years forendoscopy. The recent Scottish guidelines (15) do not suggestan age cut-off due to lack of evidence; however, they do pro-mote that an H pylori test-and-treat strategy is appropriate.Undoubtedly, clinical judgement is required (Table 2). In prac-tice, patients with new-onset dyspepsia after 50 years of agecompared with those with long-standing symptoms would beconsidered differently.

Many patients with UD will receive long-term acid sup-pression. If symptoms persist or recur frequently, it is reason-able to perform endoscopy at least once in the management ofthe patient’s disease to either confirm a suspected diagnosis

(eg, esophagitis) or rule out serious underlying disease, espe-cially cancer. Therefore, the authors’ suggestion, considering allother factors including age, symptoms, higher-risk populationsand physical signs, is that if symptoms have been present(either continuously or frequently recurring) for years, and arewithout recent change or progression, then endoscopy is likelynot required and the short-term CanDys approach may be con-sidered (1). If symptoms are becoming more severe or haverecently changed, then endoscopy must be considered.

BE and esophageal cancerBE is considered a complication of chronic gastroesophagealreflux and is a risk factor for esophageal adenocarcinoma. Thisshould be a consideration when discussing the need forendoscopy, specifically in patients with long-standing heart-burn. There is evidence for publication bias, with over-representation of studies with relatively small sample sizesreporting higher cancer risks (9,22-44). Although the RR ofadenocarcinoma (30- to 100-fold) is increased in patients withBE, the absolute risk remains low (0.4%), as does the risk ofdying from the disease (25).

The prevalence of BE (Table 3) does increase with age andis higher in males, especially Caucasians. In the CADET-PEstudy (6), the overall prevalence of histologically confirmedBE was 2.4% and 4.1% in patients with dominant heartburnor regurgitation, respectively. Because the prevalence of BE islow, it is not necessary to provide early endoscopy for patientswith dominant heartburn symptoms. Rather, one might con-sider endoscopy at a later date (using the presence of refluxsymptoms for five to 10 years, severity or ongoing need foracid suppressive therapy as an indication). Because it is diffi-cult to accurately diagnose BE when there is active inflam-mation in the distal esophagus, it is preferred that endoscopy

Management of uninvestigated dyspepsia in primary care


Uninvestigated dyspepsia

No

No

No

No

No

No

First visit

(A)

Otherpossible causes?

Consider:• Cardiac• Hepatobillary• Medication-induced• Dietary indiscretion• OtherTreat as appropriate

Yes

Yes

Yes

Yes

YesTreat as

Hp negative

(B)Age > 50 or

alarm features?• Vomiting

• Bleeding/anemia• Abdominal mess/unexpected weight

loss• Dysphagia

Investigate(endoscopy

recommended)

(C)

NSAID and/orregular

ASA use?

See NSAIDmini-management

scheme

(D)

Is dominantsymptom

heartburn and/orregurgitation?

Treat as reflux(see mini-management

scheme)

(E)

Hp test positive?1. UBT2. Serology

Treat asHp positive

Figure 1) Clinical management tool, 2000. ASA Acetylsalicylic acid;Hp Helicobacter pylori; NSAID Nonsteroidal anti-inflammatorydrug; UBT Urea breath test. Adapted from reference 1

TABLE 1Categorization of evidence, classification ofrecommendations and voting schema

Voting on recommendations

A Accept completely

B Accept with some reservation

C Accept with major reservation

D Reject with reservation

E Reject completely

Quality of the evidence

I At least one appropriately designed, randomly assigned, controlled trial

II-1 At least one appropriately designed controlled trial without random

assignment

II-2 Cohort or case-controlled studies, preferably from one or more research

groups

II-3 Substantial or marked results from uncontrolled studies

III Opinions of experts based on clinical experience or descriptive studies

Classification of the recommendations

A Good supportive evidence

B Fair supportive evidence

C Poor supportive evidence but recommendations reasonable on other

grounds

D Fair contrary evidence

E Good contrary evidence

Adapted with permission from references 1,8


be performed while the patient is on maintenance acid sup-pression therapy for his or her GERD symptoms.

While BE is managed by the specialist, it is important forthe primary care physician to understand the issues as theyapply to patients presenting with dyspepsia with or withoutdominant heartburn. In Canada, esophageal cancer is rare (in2002, 1.4% of the 68,600 new cancer cases in men and 0.6% ofthe 65,400 new cancer cases in women) and is still less fre-quent than gastric cancer (27). Over the past two decades, theincidence of all esophageal cancers has not changed. The

overall prevalence (five per 100,000) of esophageal cancer(including both squamous and adenocarcinoma) remains low,and did not increase for men and women from 1972 to 1999 (27).However, the incidence of esophageal adenocarcinoma hasmarkedly increased and now represents greater than 50% of allnew esophageal cancers. In contrast, the incidence ofesophageal squamous carcinoma has decreased. There is anincreased risk (OR 7.7) of adenocarcinoma at the gastroe-sophageal junction in those patients suffering from long-standingreflux symptoms, although the absolute risk, as noted above, islow (28). In contrast, the OR for adenocarcinoma originatingin the cardia was 2.2 (28). In that study (28), increased sever-ity, frequency (greater than three times per week), and longduration (greater than 10 to 20 years) of symptoms increasedthis OR to 16.4 to 20.

Although BE is a risk factor for esophageal adenocarcinoma,most patients presenting with cancer were not known to haveBE before their cancer diagnosis (23). Given these data andthe evidence for publication bias with over-reporting of thecancer risk, the importance of identifying BE may be overesti-mated. Nevertheless, there is limited evidence that, with sur-veillance endoscopy every few years, adenocarcinomaformation in patients with BE is detected earlier and may leadto better outcomes (16,44-47). Recent economic analyses,however, suggest that the yield of surveillance endoscopies islow and may not be cost-effective (48).

The American College of Gastroenterology guidelines (10)on surveillance for patients found to have BE are often fol-lowed; ie, endoscopy one to two years after the initialendoscopy and, if no dysplasia is detected after two endo-scopies, then endoscopy every third year thereafter. It seemslikely in the future that the screening interval may be extendedbecause most patients with dysplasia will be detected early on.More frequent surveillance is required if dysplasia has beendetected because of the link between dysplastic changes andmalignant transformation but this requires specialist care. It isimportant that if high-grade dysplasia is found, confirmation ofthe finding by a skilled gastrointestinal (GI) pathologist is gen-erally recommended. If high-grade dysplasia is confirmed,referral to a centre specialized in treatment of esophageal can-cers should be considered.

Treatment of BE aims to optimize acid suppression becausethere is compelling evidence that BE is a complication of



TABLE 3Barrett’s esophagus: Relevant data

Definition A metaplastic change from normal esophageal

squamous epithelium to columnar intestinal epithelium.

Endoscopically, this is suspected because of a

difference in the colour compared with normal

esophageal epithelium. The necessary histological

hallmark is the detection of intestinal metaplasia in

biopsies taken from the lower esophagus. When

intestinal metaplasia is accompanied by dysplasia, the

risk of malignant transformation is increased

Prevalence:

Worldwide In all patients undergoing endoscopy, the prevalence

literature is reported between 1% and 3%

In patients with long-standing heartburn, the

prevalence of Barrett’s esophagus is 3% to 5% and

in some reports as high as 6% to 12%, likely in

selected patient groups

Canadian In all patients undergoing endoscopy with heartburn,

literature the prevalence is 0.3% to 2.4%

In all patients presenting with dyspepsia, the

prevalence is 2.4% to 4.1% and 5% in those with

dominant heartburn and Helicobacter pylori-negative

Treatment Lifelong proton pump inhibitor, at least standard dose,

regardless of the presence of symptoms. Dose titrated

up, if required, to achieve adequate symptom control

Endoscopic surveillance, in accordance with

established guidelines

Adapted from references 6,10,17-19,28

TABLE 2Age cut-off: Incidence and clinical considerations surrounding gastric or esophageal cancer

Incidence (%)Risk consideration Age (years) men/women Clinical consideration

Gastric cancer <50 0.1/no data available Chronic stable symptoms for >5 to 10 years

50 to 60 0.2/0.1 Upper gastrointestinal malignancy unlikely

60 to 70 0.4/0.3 if alarm features are absent, especially if

70 to 80 0.7/0.3 <60 years

80 to 90 0.7/0.4 Is there a good therapeutic response to treatment?

Esophageal cancer – No data available Family history of upper gastrointestinal cancer?

Notes

• Gastric and esophageal cancer rates increase after 50 years of age

• Risk is greater in men than women

• There may be increased risk in subgroups such as immigrants from high prevalence regions

• Test of Helicobacter pylori infection due to associated gastric cancer risk

Adapted from references 6,9-15,17-21


chronic acid reflux (29). Treatment with a proton pumpinhibitor (PPI), usually life long, is recommended as thestandard of care for patients with BE (49). Most patientswith BE do not complain of dyspepsia symptoms such asheartburn and regurgitation, and this may be due to mucosalinsensitivity. However, PPI treatment should be maintainedin these patients even if they are asymptomatic. Similarly, ifa patient is taking once-a-day PPI and continues to havesymptoms, a dose increase can be considered. A PPI ratherthan an H2-receptor antagonist (H2RA) is recommended,given the superior level of acid suppression produced by PPIs.There is very limited evidence that PPI therapy may lead to adecrease in the length of BE or prevent its progression. Thereis one randomized controlled trial (50) comparing omepra-zole with ranitidine over two years which demonstrated thatthe PPI induced a small but significant partial regression ofBE. There is no convincing evidence that antireflux surgerymay help prevent the progression of BE to carcinoma.Referral of patients with BE for surgery is not currently the rec-ommended standard of care (51).

Recommendations1. In patients with long-standing or severe (five to

10 years, more than three times per week), dominantsymptoms of heartburn and regurgitation and/orpatients requiring long-term maintenance therapy withantisecretory medications (H2RA, PPI), a once-in-a-lifetime endoscopy is recommended.

Voting on recommendation A/9(level/vote) B/2

C/1*D to E/0

Level of evidence II-2Classification of recommendation B

*One vote was cast for accepting with majorreservation (C); this individual felt that a once-in-a-lifetime endoscopy could be performed at a later pointin time.

2. Once a diagnosis of BE has been made, guidelines forendoscopic surveillance should be followed. Currentrecommendations suggest a repeat endoscopy everythree years if no dysplasia is found after twoconsecutive annual endoscopies.


C to E/0

Level of evidence II-2Classification of recommendation C

3. The management of a patient with BE should includeoptimal acid suppression therapy, currently achievedwith a PPI using the dose that maintains completesymptom resolution.


C to E/0


ACETYLSALICYLIC ACID, CONVENTIONAL

NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS AND CYCLOOXYGENASE-2-

SELECTIVE INHIBITORSThe third step of the CMT deals with acetylsalicylic acid(ASA) or nonsteroidal anti-inflammatory drug (NSAID) use.The recommendations for NSAIDs remain unchanged exceptregarding areas involving H pylori (Figure 2).

NSAIDs, ASA and cyclooxygenase-2-selective inhibitorsCyclooxygenase (COX)-2-selective inhibitors (COXIBs) haverecently come under intense scrutiny because of evidence thattheir use may be associated with an increased risk of cardiovas-cular events. This has led to withdrawal from the market ofrofecoxib; recent reports also question whether celecoxib andperhaps valdecoxib and naproxen have similar adverse cardio-vascular side effects. It seems likely that use of all COXIBs andperhaps some NSAIDs will be re-evaluated in the near future.The following recommendations are suggested for patients cur-rently taking or being considered for COXIB or NSAID therapy.

Conventional NSAIDs are known to increase the incidenceof gastric and, to a lesser extent, duodenal ulceration, presum-ably through inhibition of the COX-1 enzyme along with thedesired inhibition of the COX-2 enzyme that is needed for itsanti-inflammatory effect. COXIBs selectively inhibit the



Yes

Can the NSAID, ASA orCOXIB treatment be

stopped?End

No

Yes

1) If taking a conventionalNSAID, consider switching toa COXIB or cotherapy with a PPI or misoprostol.

2) If taking ASA, consider cotherapy with a PPI.

3) If taking a COXIB, considerswitching to another COXIBor cotherapy with a PPI.

TESTING FOR H PYLORI INFECTIONIN PATIENTS TAKING NSAID /ASA

1) Patient has a history of (bleeding) ulcer or dyspepsia? YES

2) Patient is initiating NSAID or ASA therapy? YES

3) Patient has taken NSAID or ASA for more than 6 months? NO

1) Consider a noninvasive test forH pylori infection and treat witheradication therapy if positive.

2) If ulcer was related to ASA therapy,NSAID prophylaxis may no longerbe required if H pylori eradicationis confirmed.

3) If ulcer was related to conventionalNSAID therapy, NSAID prophylaxisis required, despite H pylori status.

Is the patientimproved?

Yes

Does the patient havea prior history of gastric

or duodenal ulcer?

No

Figure 2) Nonsteroidal anti-inflammatory drug (NSAID) mini-management scheme. ASA Acetylsalicylic acid; COXIBCyclooxygenase-2-selective inhibitor; PPI Proton pump inhibitor.Adapted from reference 1

vanzanten_8678.qxd 4/29/2005 9:29 AM Page 289

COX-2 enzyme but spare the activity of the COX-1 enzyme; asa result, it has been postulated that there is considerably lessulcerogenic potential with the COXIBs (52). The benefit ofCOXIBs appears to be substantial for ulcers, but is much less fordyspepsia symptoms in comparison with conventional NSAIDs(53,54). Indeed, there continue to be questions regarding theuse of COXIBs, NSAIDs and ASA and the development of dys-peptic symptoms. All these agents can cause dyspepsia and/orulceration; however, no clinical data exist to guide managementfor scenarios where patients are switched from conventionalNSAIDs to a COXIB (55,56). Data on the frequency ofNSAID-induced dyspepsia are limited. A meta-analysis (57)found that indomethacin, meclofenamate or piroxicam at anydose, and other NSAIDs at high dose but not at low dose,increased the risk of dyspepsia threefold. However, there is evi-dence (58) that ASA increases the risk of dyspepsia (OR 1.36)compared with placebo. Of note, GI hemorrhage occurs in2.47% of those taking ASA (50 mg to 1500 mg) compared with1.42% of nonusers, representing an OR of 1.68 (59). An OR of1.59 was reported for those taking doses of ASA below 163 mg/day (59). Unfortunately, there are no studies that pro-vide the incidence rate of dyspepsia when patients initiate ASAtherapy. Conventional NSAIDs cause dyspepsia at a rate of 13%to 36%; the wide range is largely the result of varying study def-initions of dyspepsia (60). The COXIBs (currently celecoxib,rofecoxib and valdecoxib) can also cause dyspepsia. For cele-coxib, the reported cumulative six-month dyspepsia rate was16.5% compared with 19.5% for traditional NSAIDs (53). Forrofecoxib, the cumulative six-month dyspepsia rate was 23.5%compared with 25.5% for traditional NSAIDs (54,61).Valdecoxib, which has recently become available, also can causedyspepsia (62-65). The data on etoricoxib are at this point toopreliminary to draw any conclusions (66). If ongoing anti-inflammatory or antiplatelet therapy is required, a switch to aCOXIB can be considered or a trial of a PPI added.

There are no available clinical trial data surroundingimprovement of dyspepsia on switching from a conventionalNSAID to a COXIB. Essentially, the prevalence of dyspepsiawhile taking a COXIB is slightly lower compared with a con-ventional NSAID in some reports (53,54), and is not differentaccording to other reports (61,62,64,65). This recommenda-tion is based solely on expert opinion; there are no publisheddata available to support that such a switch improves dyspepsia.The difficulty with ASA-associated dyspepsia is that it may bedifficult to discontinue the ASA therapy if it is being takenbecause of a well-established cardiac or neurological risk.Clearly the benefits and risks of ASA therapy need to be dis-cussed with the patient and may vary depending on whetherone is dealing with primary or secondary prophylaxis for neu-rological or cardiac disease.

Currently, there is much interest and uncertainty regardingpatients taking both an NSAID (or COXIB) and ASA. Thisissue became evident in the Celecoxib Long-term ArthritisSafety Study (CLASS) (53), a large clinical trial of celecoxiband two conventional NSAIDs, which evaluated serious GIevents. In this study, there was evidence that, in patients takingcelecoxib, concurrent therapy with ASA abolished the protec-tion against GI complications that was provided by treatmentwith the COXIB alone. The possible explanation for this isthat concurrent use of ASA blocks the COX-1 pathway,thereby negating protection against gastroduodenal injury pro-vided by the COXIB (67). Further studies are required to clarify

the possible interactions between ASA and COXIBs.Cotherapy of a COXIB with a PPI or misoprostol may beappropriate but there are no studies that have specificallyaddressed this.

Interaction between NSAIDs and H pylori

There now is evidence for synergy between concurrent conven-tional NSAID treatment and H pylori infection in causingulcers (68-71). The interaction is stronger for duodenal thangastric ulcers (68). There is evidence from one Hong Kongstudy (71) that, for selected patients diagnosed with an ulcer(the study was not directly applicable to patients with UDsymptoms) who were taking ASA, eradication of H pylori was aseffective in preventing recurrent ulcers as PPI cotherapy. This isin contrast to results using conventional NSAIDs, which arestill associated with recurrent ulcers (19%) when used after cureof H pylori infection. However, a second study (71) from HongKong did not find the same rate of protection in ASA-associatedulcers although, in that study, most bleeding ulcers occurred inH pylori-positive patients not cured of their infection, orpatients taking concurrent NSAID therapy. Studies are neededin North America to clarify these intriguing findings. Theseconsiderations support the practice of NSAID primary or sec-ondary prophylaxis, with a PPI or misoprostol, for preventingpeptic ulcer complications according to a patient stratificationscheme based on the presence of risk factors (age over 65 years,previous peptic ulcer bleed, corticosteroid use, concomitant useof anticoagulation therapy, frailty). Patients on both an NSAIDand ASA may be at an even greater risk although there are lim-ited data for this specific situation (72). Here it is important toemphasize that most of the above data focus on patients withknown ulcer complications. This population differs from theprimary care patient population with uninvestigated symptoms,which is inclusive of this subgroup, and is the subject of the cur-rent paper. It therefore requires consideration when imple-menting any management approach because a decrease in ulcerrisk is clinically important and many, but not all, ulcer cases areassociated with dyspepsia (73-78).

Given the interactions between NSAIDS and H pylori,the recommendation in patients who are starting, or haverecently (under six months) started, an extended course ofcontinuous therapy with conventional NSAIDs or ASA, is totest for H pylori and subsequently confirm eradication. Thereare no data on ulcer and dyspepsia incidence in H pylori-positive patients taking COXIBs. For rofecoxib, data from theVioxx Gastrointestinal Outcomes Research (VIGOR) study(76) were analyzed according to H pylori status and no inter-action was found between H pylori infection and rofecoxibtherapy in causing serious GI events. Ulcers were, however,more common in H pylori-positive patients. For celecoxib, nodata stratified by H pylori status are available. Checking forcure of the infection is important because a decreased risk ofulcer and its complications will not be observed if the infec-tion persists. Testing is strongly recommended if patientshave a history of previous ulcers, ulcer bleeding, or are diag-nosed with a gastric or duodenal ulcer while on ASA, a con-ventional NSAID or a COXIB. However, while the risk isdecreased by H pylori eradication, it is not abolished com-pletely. Although results from the Hong Kong studies needfurther confirmation, the data suggest that patients takingASA will not need gastric cytoprotection if they are H pylori-negative. In contrast, patients on conventional NSAIDs still




need prophylaxis despite being H pylori-negative because the riskof ulcer remains high. There are no data available to guide man-agement in patients taking COXIBs who are H pylori-negativeafter eradication therapy.

Testing is not routinely recommended in long-term (overone year) NSAID or ASA users who have not experienceddyspepsia or ulcers because the risk of ulcer bleeding complica-tions is low in patients who have not had a bleed within theirfirst year of use (68,70). Caution is warranted if an NSAID isprescribed to a patient already taking ASA (or vice versa)because the second medication may increase the ulcer risk(77,78). More data are needed on the interaction betweenASA and either conventional NSAIDs or COXIBs to provideclarification in this area.

Recommendations4. Conventional NSAIDs or COXIBs can be a cause of

dyspepsia. Preferably the drug should be discontinuedto determine whether the dyspepsia resolves.

Voting on recommendation A/12(level/vote) B to E/0

Level of evidence IIIClassification of recommendation C

5. If stopping the NSAID or COXIB is not possible,consider switching to a different NSAID or COXIB.


C to E/0


6. If the NSAID or COXIB cannot be stopped, cotherapywith a PPI, misoprostol or high-dose H2RA may beconsidered, although the evidence is for ulcerprophylaxis and not dyspepsia.


C to E/0

Level of evidence I (NSAID)II-2 (COXIB)

Classification of recommendation C

7. If the ASA cannot be stopped, cotherapy with a PPIshould be considered.


C to E/0

Level of evidence IClassification of recommendation B

8. Testing for H pylori infection is stronglyrecommended, and proof of eradication advised, ifpatients have a history of previous ulcers, ulcerbleeding, or are diagnosed with a gastric or duodenalulcer while on ASA, a conventional NSAID or aselective COXIB.


C to E/0

Level of evidence II-2 (ASA)II-3 (NSAID)III (COXIB)


GERD AND HEARTBURN SYMPTOMSInitial patient management – further evidenceThere are only limited direct data on the comparison of dif-ferent empirical therapies in uninvestigated patients withreflux symptoms in a primary care environment. A recentmeta-analysis (79) of primary care patients with dominantheartburn has shown that the benefit of PPI over H2RAtherapy was larger for nonendoscoped compared with inves-tigated patients. Due to the paucity of data, recommenda-tions for the management of heartburn-dominant UD aremade by extrapolation from the combined healing andsymptom resolution results of studies in patients with ero-sive esophagitis or nonerosive reflux disease (NERD, alsoreferred to as endoscopy-negative reflux disease).

There are conclusive data from acute and long-termstudies (80-84) that PPIs provide significantly better healingand symptom relief than H2RAs (or cisapride) for erosiveesophagitis. Similarly, standard-dose PPI is also more effec-tive than low-dose PPI (85-87). Therefore, treatment with aPPI is listed as the first choice. Because there is evidencethat a greater proportion of patients will respond to acid sup-pressive therapy after eight weeks compared with four weeks,it is reasonable to re-evaluate patients after four to eightweeks of initial therapy (80,83,86). The decision whether toinitiate therapy with a PPI or H2RA should be made after acareful discussion with the patient. However, if an H2RA ischosen and the response is inadequate after four to eightweeks, the patient should be switched to a PPI. With respectto heartburn-dominant UD, the superiority of PPIs was docu-mented in a meta-analysis (79) of empirical therapy forGERD, and this analysis also suggested that low-dose PPIs areless effective than standard-dose PPIs for empirical therapy.There are data showing small differences between PPIs withrespect to healing, symptom relief and maintenance of remis-sion in patients with erosive esophagitis, but the implica-tions of these findings have yet to be established forsymptom management in the larger population of patientswith heartburn-dominant UD (87-89).

The recently completed CADET Heartburn-Dominant(CADET-HR) study (83) compared initial therapy with a PPIor H2RA followed by on-demand treatment with a PPI orH2RA on relapse of symptoms. The results from this study sup-port that a PPI provides better symptom relief than an H2RA.After four to eight weeks of treatment, relief of heartburn was55% for those started on a PPI compared with 27% for thosestarted on an H2RA. Of patients started with an H2RA, 47%needed to be stepped up to a PPI due to inadequate symptomrelief. Comparatively, 26% of those starting with a standard-dose PPI needed to be stepped up to higher dose PPI treatment.

For patients with erosive esophagitis, symptom relief atfour weeks in response to treatment with a PPI was associatedwith healing of esophagitis in approximately 80% ofpatients (80). There are Canadian data in uninvestigated




patients with heartburn-dominant or -nondominant dys-pepsia that show that a longer duration of treatmentimproves the response rate. Data from the CanadianConfirmatory Acid Suppression Test (CAST) study (90)showed a significant increment in symptom resolution iftreatment with esomeprazole 40 mg once a day was extendedfrom one to four and eight weeks in patients with heartburn-dominant UD. Thus, the response to initial therapy with aPPI should be evaluated after four to eight weeks of treat-ment although, in cases where symptoms continue to beunacceptable after four weeks, the physician may choose toreview the patient sooner.

The role of endoscopy in dyspepsia patients with long-standing dominant heartburnIn large cohorts of patients in managed care populations,approximately 2% to 3% have chronic acid-related disorders(91-93). If a patient is unable to discontinue acid suppressivetherapy or has been on acid suppressive therapy for five to10 years, he or she should be considered for referral forendoscopy if this has not been performed previously. Becausethere is some evidence that patients have a fear of seriousunderlying disease (eg, cancer), a normal endoscopy canprovide important reassurance to the patient and physician(94,95). A discussion between the patient and physicianshould include the fact that the risk of serious disease is low

and this may help in the decision around the request for andtiming of an endoscopy. In patients with long-standing heart-burn, the main indication for endoscopy is to exclude compli-cations of esophagitis such as stricture, BE or dysplasia (16).

RecommendationPlease refer to “BE and esophageal cancer – Recommendation 1”

The patient with symptoms of heartburn and acid regurgitationfor five to 10 years who has a normal endoscopy without evi-dence of BE requires no further follow-up endoscopy unless symp-toms change or alarm features develop (96-99). There are no datato indicate that younger patients with a normal endoscopyshould have a repeat endoscopy later in life. This recommenda-tion assumes that patients receive optimal acid suppressive ther-apy for control of their symptoms, defined as treatment that leadsto complete or near complete control of symptoms.

Long-term management options for patients with dominantheartburnMedical options for long-term therapy in patients with recur-rent symptoms include continuous, intermittent or on-demanduse of drugs (Figure 3). Long-term therapy with PPIs andH2RAs has been demonstrated to be effective and safe (100-106).If PPIs are used initially, then consideration may be given tosubsequently trying an H2RA, although data to support suchan approach are limited (107,108). There is evidence that asmall proportion of patients can tolerate stepping down but, inthe majority of patients, the data show that step-down treat-ment should not be considered because it leads to worsening ofsymptoms (107,108). Step-down treatment should not beattempted if the patient remains symptomatic on PPI therapy.

Patients with reflux esophagitis or NERD have a refluxsymptom relapse rate of over 80% after therapy is stopped.Relapse usually requires medication, either continuously orintermittently, for control. It is reasonable to attempt with-drawal of regular therapy for GERD because a small proportion(less than 20%) of these patients does not need any pharmaco-logical intervention when assessed at six months to one year(107-110). In the CADET-HR study (83), 75% of thesepatients relapsed within eight to nine days after first becomingsymptom-free and stopping their medication. Thus, the major-ity of patients will require some form of maintenance therapy.

On-demand therapy, for which patients only take medica-tion during periods when they are experiencing symptoms, isattractive because it leads to decreased use of medication and,hence, drug-related costs. However, data are only available forpatients with NERD and not UD (111-116). Alternatively,intermittent dosing (a daily two- to four-week course takenwhen symptoms recur) is a consideration, but this has onlybeen studied in duodenal ulcer patients before the era of H pyloriinfection (110,116).

Antireflux surgery as a long-term management approach isan option for patients who require ongoing medication to con-trol their symptoms or in those who have ongoing symptomsdespite medical therapy (37,117). Indications for surgery arechanging but a 1999 multivariate analysis (118) concludedthat the patients who benefitted the most from an antirefluxprocedure were those whose symptoms were already controlledon medical therapy. In that study, the best predictors, in orderof success, were: 24 h abnormal pH profile, heartburn as thedominant symptom and response to medical therapy. In



**Adequate symptom control is the goal regarding any treatment strategy

Consider endoscopy for the detection of Barrett’s esophagus if chronic symptoms of GERD have beenpresent for more than 5 to10 years:1) If no Barrett’s mucosa is detected → no follow-up endoscopy is required2) If Barrett’s mucosa is found → offer patient participation in a surveillance program

Chronic symptoms ofheartburn and/or regurgitation

Treat for 4-8 weeks: 1) PPI 2) H2RA

Yes

Symptomsresolved after

1 month?

Stop therapy.If symptoms recur

resume same therapywhich resulted insymptom relief

Is adequate reliefobtained?

No

Yes

Is adequate relief obtained?Continue same

treatmentYes

Treatment change:1) If not on a PPI,

switch to a PPI2) If on a PPI, double

PPI dose to bidfor 4 to 8 weeks

3) Consider investigation(endoscopy)

Consider treatment change:1) Continue treatment as is2) If on a PPI, consider

step-down to an H2RA3) If on an H2 RA, consider

step-down to prn4) Consider intermittent

treatment with a PPI

Treat with once daily medication thatrelieved symptoms before

No

Figure 3) Reflux mini-management scheme. bid Twice daily; GERDGastroesophageal reflux disease; H2RA H2-receptor antagonist; prnAs needed; PPI Proton pump inhibitor. Adapted from reference 1

vanzanten_8678.qxd 4/29/2005 9:29 AM Page 292

Canada in 1996, the rate of antireflux surgical therapy was11.4 (7.5 abdominal, 0.9 thoracic, 3.0 laparoscopic) per100,000 population, with a 5.5% average increase in the use oflaparoscopic procedures between 1992 and 1996 (119). Fewhead-to-head comparisons (120-126) of open versus laparo-scopic antireflux procedures have been reported. Functionaloutcomes, up to two years, appear comparable between the twoprocedures; however, there is no long-term outcome compar-ison available. Lundell et al (127) reported their five-yearfollow-up of a randomly assigned clinical study comparingopen antireflux surgery with continuous omeprazole therapy.Overall quality of life did not differ between the two groups,but the surgical group had more dysphagia and inability tobelch than the medical group. During long-term follow-up(mean 10.6 years), more than 40% of operated patientsrequired acid suppression for symptom control (125). In addi-tion, this study reported that laparoscopic fundoplication has asmall (less than 1%) but definite risk of serious complications.CanDys recommends that antireflux surgery only be consid-ered in a small proportion of patients and only after a thoroughspecialist investigation.

Novel endoscopic techniques have been recently devel-

oped that create a barrier to reflux by enhancing lower

esophageal sphincter (LES) pressure. These techniques use

suturing, injection of a biopolymer or creation of tissue dam-

age using a high radio frequency stimulator at the gastroe-

sophageal junction. There are no head-to-head comparative

studies of current treatment alternatives; data (128-130) are

short-term with suboptimal selection of outcomes. None of

these treatment modalities can currently be recommended in

routine practice.

Recommendations9. Patients with frequently recurring symptoms of

dominant heartburn and/or regurgitation should betreated with the same treatment that led to adequatecontrol during initial treatment.


C to E/0

Level of evidence IClassification of recommendation A

10. In patients with dominant symptoms of heartburnand/or regurgitation, maintenance therapy with a PPIis more effective for symptom control than with anH2RA, for both acute and long-term therapy.



11. Antireflux surgery should only be considered for thosewho are unable or unwilling to take long-term acidsuppressive medication.


C to E/0

Level of evidence I

Classification of recommendation A

Management of patients with long-standing dominantheartburn and H pylori infectionIn Canada, the overall prevalence of H pylori infection is 25% to30% (6). Age is an important risk factor. Most studies, includingCADET-PE (6,131-134), have shown a lower prevalence ofH pylori infection in patients with esophagitis compared withthose without. H pylori-infected patients may have gastritis inthe body of the stomach which may decrease gastric acid out-put and thereby lower the potential for acid reflux and resultantesophagitis. There has been controversy over whether cure ofH pylori infection might provoke or lead to worsening of GERD.Most of the evidence (135-140) shows that this is not the case.

Patients with GERD who require long-term acid suppres-sion, especially with a PPI, and who are infected with H pylori,have a worsening of gastritis in the body of the stomach (141).This deterioration of histological gastritis is not seen in H pylori-negative patients taking PPIs or in those in whom H pylori infection has been cured (142-147). Several randomlyassigned controlled trials (148,149), however, have shown thatcure of the H pylori infection leads to regression of the body gas-tritis. To date, there is no evidence that the deterioration ingastritis has serious long-term consequences (such as gastriccancer). Hence, it is the CanDys recommendation that a rou-tine ‘test for H pylori and treat if positive’ strategy is not neces-sary in patients requiring long-term PPI therapy (over oneyear).

Recommendation12. Routine testing for H pylori is not required for patients

on long-term PPI therapy. However, it is reasonable todo so on a case-by-case basis.


C/1D/1E/0


Management of patients with nonheartburn-dominantdyspepsia and H pylori infectionThe CMT recommendation for patients with dyspepsia whoare not using NSAIDs or ASA and who do not have dominantsymptoms of heartburn is a noninvasive test for H pylori, andtreatment if the test is positive. The CADET H pylori(CADET-Hp) study (3) compared a one-week PPI-based erad-ication regimen with placebo (empirical twice-a-day PPI)treatment given for one week, to determine whether H pyloritreatment does lead to long-term improvement in dyspepsiasymptoms. This study of 296 patients showed that there wassymptomatic improvement at 12 months in 50% of patients, inwhom H pylori infection was cured, compared with 36% ofcontrols with persistent infection (P=0.02). The number neededto treat to achieve one long-term success was seven patients. Itis important to note that while all patients presented with aprimary complaint of epigastric pain, a proportion (30%) ofthe patients also had dominant heartburn and/or regurgitation.




A post hoc subgroup analysis suggested that, in a small popula-tion of patients, heartburn symptoms will improve afterH pylori eradication. The benefit of curing H pylori has beensupported in other studies as well (150-153). The benefits ofthe test-and-treat approach are probably derived mainly fromtreatment of underlying ulcer disease and possibly improving asmall proportion of functional dyspepsia patients (150-153).The lifetime risk in an H pylori-infected individual to developulcers is 5% to 15% (154,155). It is important to note that,despite successful treatment of the infection, a substantial pro-portion of patients (at least 50%) will require ongoing treat-ment for dyspepsia symptoms. In such cases, three optionsexist: retest for H pylori infection using a urea breath test(UBT) to ensure the infection has been cured; institute empir-ical therapy in accordance with the CMT recommendations;or perform endoscopy if clinically indicated, at which timebiopsies for H pylori infection should be taken.

Recommendation13. In patients with dyspepsia who do not have alarm

symptoms or symptoms of dominant heartburn or acidregurgitation, and are not using NSAIDs or ASA, atest for H pylori should be ordered and the patienttreated if positive.


C to E/0


TREATMENT OF H PYLORI INFECTIONTreatment, as recommended in the CMT (1), consists oftriple therapy with a PPI twice a day, clarithromycin 500 mgtwice a day and either amoxicillin 1000 mg twice a day ormetronidazole 500 mg twice a day. Recently, it has been rec-ommended that PPI-clarithromycin-amoxicillin be used first-line because that combination is unaffected by resistance tometronidazole. Although there are limited data, the preva-lence of metronidazole resistance in Canada is estimated tobe approximately 20% (156-160). First-line use with ametronidazole-containing regimen is a reasonable alternativefor patients with a penicillin allergy. Regarding the durationof eradication treatment, the recommendation continues tobe seven to 10 days for the first treatment (161,162). Recentdata (156,163,164) suggest that bismuth-based quadrupletherapy may be as effective as PPI-based triple therapy and,therefore, could be considered as an alternative first-linetherapy. However, this therapy is more complicated andinvolves taking 18 tablets a day. All PPIs available in Canada(esomeprazole, lansoprazole, omeprazole, pantoprazole andrabeprazole) have similar efficacy in curing H pylori with com-binations of clarithromycin-metronidazole or clarithromycin-amoxicillin (165-167). Eradication failure is a concern becausePPI-clarithromycin-amoxicillin or PPI-clarithromycin-metronidazole combinations are not successful in 15% to 25%of cases (168). Quadruple therapy (PPI twice a day, bismuthsubsalicylate two tablets four times a day, tetracycline 500 mgfour times a day and metronidazole 250 mg to 500 mg fourtimes a day) for 10 to 14 days is the preferred therapy forH pylori treatment failures (156,164,168).

Recommendations14. Patients who are H pylori-positive should be treated with

a combination of PPI, clarithromycin and amoxicillin forseven to 10 days. PPI-clarithromycin-metronidazole canbe used if the patient is allergic to penicillin.



15. Quadruple therapy (PPI plus bismuth-metronidazole-tetracycline) for 10 to 14 days is an acceptable first-linealternative.



Diagnostic tests for H pylori

The most frequently used diagnostic test for H pylori infection isserology. The UBT is recommended because it has a higher pos-itive predictive value (predicting the true presence of infection)and negative predictive value (predicting the true absence ofinfection) compared with serology, over a broad infection preva-lence range (169,170). However, the UBT is not readily avail-able across Canada and access may be limited due to lack ofreimbursement. For serology, the negative predictive value ishigh (over 90%) while the positive predictive value is reducedto 70% to 80%, especially in individuals less than 40 years of agewho have a lower (less than 20%) H pylori prevalence (170).This means that when serology is used, a significant proportionof patients will be treated based on false-positive test results.

The European Helicobacter pylori Study Group has recom-mended use of the stool antigen test of H pylori detection(171). This procedure has not been adequately tested and isnot available in the primary care setting (or most secondaryor tertiary settings) in Canada and, therefore, is not recom-mended by CanDys.

Testing for H pylori infection following treatmentIt is not mandatory to routinely test patients following an erad-ication attempt unless they have ongoing or recurrent symp-toms (171). Testing for cure of H pylori should be performed inall patients who have had a bleeding ulcer, and acid suppres-sion therapy should be continued until it is determined thatthe patient is H pylori-negative, with the caveat that theyshould discontinue PPIs seven to 14 days before a UBT to min-imize the risk of a false-negative study. Serology is not anacceptable follow-up test because antibodies may remaindetectable for over 12 months despite successful cure of theinfection (170). If UBT is not available, endoscopy with biop-sies may be performed to document cure if the endoscopy isclinically indicated. Should the patient continue to be H pylori-positive, retreatment with an alternative eradicationtherapy is recommended.

In Canada, the success rate of H pylori eradication treatmentis high (75% to 85%) and, therefore, it is likely that, once treat-ed, patients will become H pylori-negative. Acid suppressivetherapy is the treatment of choice for ongoing symptoms, and itis reasonable to start this treatment as soon as the patient




returns for management of symptoms rather than awaiting theresults of further H pylori testing.

It is recognized that PPIs suppress H pylori, although cure ofthe infection with PPI monotherapy is very rare (172,173). Upto 20% of patients may test falsely negative for the infection ifPPIs are used at the time that a UBT is performed (174-180).The recommendation is to stop PPIs for 14 days before theUBT (181,182). In practice, this may be difficult because somepatients will have worsening of symptoms during this interval.Often this can be bridged with the use of antacids. For H2RAs,the recommendation is to stop for seven days before testingbecause they too can have an effect on H pylori (183,184). Inpractice, it may be reasonable to use two weeks as a guidelinefor all such medications. Antimicrobials and bismuth com-pounds must be discontinued for four weeks before a UBT toavoid false-negative test results.

Recommendations16. Patients who have ongoing or recurrent dyspepsia

symptoms following H pylori treatment should betested by UBT (not serology) or undergo endoscopywith biopsies to determine whether H pylori is present.


C to E/0


17. If the patient continues to test positive (not serology)for H pylori infection, retreatment with an alternativeregimen should be given, for which quadruple therapyis the treatment of choice.


C to E/0


18. If the patient retests negative, he or she should betreated as an H pylori-negative dyspepsia patient withacid suppression as defined in the CMT.


C to E/0


Management of H pylori-negative patientsThe CMT recommends treatment for four to eight weeks witha PPI or H2RA for H pylori-negative patients who are not usingNSAIDs or ASA, and whose symptoms do not suggest GERD.There is evidence (185-191) that, for this patient group, a PPIprovides superior efficacy compared with an H2RA or a proki-netic agent. As well, a greater proportion of patients willrespond after eight weeks of treatment, compared with afterfour weeks (85).

Few long-term efficacy studies have been published in H pylori-negative dyspepsia patients; however, available dataindicate that PPIs provide better efficacy compared withH2RAs. The CADET H pylori-negative (CADET-HN) study

(188) compared a PPI, an H2RA, a prokinetic agent and placeboin uninvestigated H pylori-negative dyspepsia patients. Afterfour weeks of continuous treatment, those given a PPI had asuperior response (51%) relative to that of the other threetreatments (36%, 30% and 23%, respectively; P=0.01). Thisstudy had a five-month follow-up phase during which patientscontinued the same drug in an on-demand fashion. Responserates in the on-demand phase, during which patients on aver-age took medication every other day, were not as high as dur-ing the acute treatment phase. The proportion of patientswho were responders at both four weeks and six months were:omeprazole 31%, ranitidine 21%, cisapride 13% and placebo14% (P<0.05, omeprazole versus cisapride or placebo).

The CMT was published in June 2000 when the prokineticagent cisapride was still available. This agent has since beenwithdrawn from most markets due to rare but possibly life-threatening cardiac arrhythmias. Cisapride is currently avail-able only under special authorization for patients with severegastroparesis; it should not be used for the treatment of dys-pepsia. For the two other available prokinetic agents (dom-peridone and metoclopramide), there is very limited evidence(190,191) regarding efficacy in dyspepsia. However, in clinicalpractice, patients who do not respond to high-dose acid sup-pression therapy are often tried on prokinetic agents despitelimited published clinical data to support such an approach.

Recommendations19. Patients with H pylori-negative dyspepsia should be

treated with a course (four to eight weeks) of acidsuppressive therapy as recommended in the CMT.



20. In patients with H pylori-negative dyspepsia, PPIs aremore effective than H2RAs in symptom control, forboth acute and long-term therapy.



Management of nonrespondersIn the case of a patient (either heartburn-dominant or non-heartburn-dominant H pylori-negative) with only partial orno symptom response to a course of standard-dose acid sup-pression, the CMT recommends to increase the degree ofacid suppression to a PPI if an H2RA was given, increase thedose of a PPI to twice a day, or treat for a further four to eightweeks with the same dose. There are no clinical trial data forthe last approach. If a patient fails to improve with a courseof double-dose PPI for four to eight weeks, it is unlikely thatthe symptoms are acid-sensitive, and the PPI should be dis-continued, symptoms reviewed and the patient investigatedfurther (eg, endoscopy).

Recommendation21. If, after a course of initial standard-dose acid

suppression, a patient does not respond to a further




four to eight weeks of high-dose PPI, then furtherinvestigations, such as endoscopy, may be required.



Management of partial respondersIt is uncertain how to manage patients with a partial sympto-matic response. There is no set definition for a partial response;however, it can typically be defined by one or more of the fol-lowing: incomplete symptom control, return clinic visits orunwillingness to continue prescribed therapy. Medication com-pliance may play a role because there is a theoretical advantageto the administration of PPI once a day (in the case of a singlestandard dose) given 30 min to 60 min before breakfast, the timewhen acid pumps are most readily blocked (192-195). It isrational to consider a switch in medication or increase in dose ofthe treatment for another four- to eight-week period (if on anH2RA, switch to a PPI and if on a PPI, give a higher split dose),despite lack of supportive data for this approach.

Recommendation22. If a patient has not responded, or has only partially

responded, to a four- to eight-week treatment with anH2RA or a PPI, consider switching to a PPI if thepatient was on an H2RA, or if on a PPI, doubling thedose of the PPI for another four to eight weeks.


C to E/0


OTC medicationsSeveral epidemiological studies (196) have shown that a highpercentage of people with dyspepsia have tried OTC productsas an initial step in management of their symptoms. OTCdrugs include antacids, alginate-based products, H2RAs, bis-muth products and herbal products. Published studies of theseagents include few randomly assigned controlled trials andrelate to a broad spectrum of patient populations, primarilyfunctional dyspepsia or heartburn-predominant dyspepsiapatient populations.

Antacid products have been shown to provide sympto-matic relief of heartburn in some but not all studies (197),but have no effect on healing of erosive esophagitis. Theymay provide more prompt symptom relief than OTC doses ofH2RAs (198). Thus, the evidence suggests that antacidsshould be used for unpredictable episodes of heartburn andfor symptomatic ‘breakthrough’ episodes of heartburn.Several studies (199,200) suggest that the benefit of antacidsprobably stems from their ability to provide intraesophagealneutralization of acid rather than neutralization of acid presentin the stomach. H2RAs in OTC formulations containing one-half of the prescription strength product per unit dose (eg, rani-tidine 75 mg, famotidine 10 mg) do lower gastric acid secretion(201,202). Randomly assigned controlled trials (203-206) of

these agents (low-dose OTC cimetidine, ranitidine, famotidine)have shown that these products produce significantly greaterrelief or prevention of postprandial reflux symptoms thanplacebo. These drugs are well-tolerated with few side effectsreported. The ideal use of the OTC H2RAs is to administer thedose 1 h to 2 h before episodic and/or predictable occurrences ofheartburn, such as before meals (27).

Alginate-based products (Gaviscon, GlaxoSmithKline,USA) are approved for heartburn relief only. Both in vitro and invivo studies (207) have shown that these agents produce theirbenefit by forming a ‘raft’ or foamy physical barrier that may pre-vent gastroesophageal reflux. Alginate products must be takenapproximately one-half hour after meals to produce this effectand subsequent benefit; taking these products before or duringmeals destroys the ability of the alginate to form an effective raftto reside on the gastric contents. Clinical trials (204) demon-strate that various alginate formulations produce heartburn reliefsignificantly better than placebo; comparisons with antacidshave produced varying results of benefit of one over the other.

Many herbal product manufacturers and distributors claimefficacy for their products in dyspepsia; however, there are fewwell-designed randomly assigned controlled trials (208) thatsubstantiate this, and most of these studies are in patients withfunctional dyspepsia. Only studies of products containing acombination of peppermint and caraway oils reported benefitover placebo, but the evidence is insufficient to support anyrecommendations.

In all instances when OTC medications do not provideadequate symptom relief for the patient, or symptoms occurfrequently, patients should be advised to consult their familypractitioner for further discussion and assessment of dyspepsiasymptoms.

Recommendations

23. For infrequent or unpredictable episodes of dyspepsia,

OTC medication can provide relief.

Voting on recommendation A/7

(level/vote) B/5

C to E/0

Level of evidence I

Classification of recommendation B

24. If the requirement for OTC medications is frequent

and/or symptoms influence daily living, then a

physician should be consulted.

Voting on recommendation A/12

(level/vote) B to E/0

Level of evidence III


Pregnancy and lactationDyspepsia in pregnancy is common, with heartburn and acidregurgitation reported by 45% to 80% of pregnant women asthe most bothersome GI symptoms, especially in the latter halfof the pregnancy (2109-210). The high frequency of refluxsymptoms likely occurs as a result of increased abdominal pres-sure due to the growing gravid uterus and a decrease in LESpressure caused by changes in hormonal status (211,212).There is good evidence (213) that abnormal LES pressure




normalizes soon after delivery. There is obvious concern aboutthe use of medications in pregnancy up to the 14th week dur-ing organogenesis when teratogenic risks are greatest andtherefore have the most potential to damage the fetus. TheMotherisk program (http://www.motherisk.org/) may be con-sulted, accordingly, for drug-specific or breastfeeding informa-tion. Recommendations related to drug use in pregnancy stemfrom data in animals regarding potential teratogenicity. Thereare data from randomly assigned and nonrandomly assignedstudies and reviews in pregnancy (214-222) but their numbersare small. Antacids should be tried first. An H2RA may be pre-scribed if antacids fail to provide adequate relief. Most of thesafety data for for H2RAs is for ranitidine. Should H2RAs notsuffice, a PPI can be considered. For PPIs, most of the datacome from small cohort studies in women using omeprazole(214). Other data (223) suggest that there is no evidence ofmeasurable teratogenic risk, increased risk of abortion or risk oflow birth weight in humans with the use of H2RAs (particu-larly ranitidine) or PPIs (particularly omeprazole) during preg-nancy. It must be noted that there are limited data with regardto these recommendations and, as such, very judicious andcareful use of such medications is required. Meta-analysis data(214) of the Motherisk program suggest that omeprazole is safe.However, the Food and Drug Administration has assignedomeprazole a category C (human data lacking; animal studiespositive; or not performed) based on animal data, suggestingpossible toxicity in embryos using high doses of omeprazole.This in contrast to lansoprazole (Food and DrugAdministration category B: human data reassuring [animal-positive]; or animal studies show no risk) where animal datadid not show toxicity (224).

For breastfeeding, the recommendation is to initially tryantacids, followed by an H2RA and then a PPI. For both H2RAsand PPIs (data are only available for omeprazole), there is evi-dence (225) that they are excreted in breastmilk but their levelsare low and considered unlikely to be of clinical consequence;PPIs, therefore, probably can be used safely. As with all medica-tions, these drugs should only be used if the symptoms are suffi-ciently severe to require treatment.

Recommendation25. In pregnancy, or when breastfeeding, treatments for

dyspepsia symptoms should be used in the followingorder:

a) Antacids

b) H2RAs (most data available for ranitidine) or PPIs(most data available for omeprazole)


C to E/0

Level of evidence II-2Classification of recommendation B

Dyspepsia and psychosocial factorsMost evidence correlating psychosocial distress with dys-pepsia arises from studies (226,227) of investigated, func-tional (nonulcer) dyspepsia. Patients consulting fordyspepsia are more likely to have experienced psychosocial

stress in the preceding six months (228). Socioeconomicchallenges, low expectations, depression and less optimismare predictors of poor outcomes in functional dyspepsia(228). Health-related quality of life, measured at one year,is more closely linked to psychological distress than to theseverity of dyspepsia (229). Addressing psychological factorscan have an important impact on the long-term outcome ofrelated dyspepsia symptoms (227). Although there are nospecific data from UD studies, it is reasonable for the physi-cian to determine psychological stressors when a patientpresents.

Antidepressants and psychological interventionsApart from improving mood, antidepressants have also beenused in the treatment of functional GI disorders such as irrita-ble bowel syndrome, noncardiac chest pain and functional(investigated) dyspepsia (230). The limited evidence for UDpatients in this area precludes any recommendation. There isemerging evidence on selective serotonin reuptake inhibitortreatment and the apparent risk of peptic ulceration associatedwith its use; however, the data (231,232) centre on the risk ofGI bleeding rather than dyspepsia. There are no treatmentdata in UD evaluating the effect of psychotherapy or other psy-chological treatment. It is self-evident that, if mood distur-bance presents as a health concern, then it should be discussedwith the patient (233).

CONCLUSIONSThe CMT described in the present paper provides evidence-based recommendations for both the acute and long-termmanagement of UD patients. In addition to recommenda-tions for patients taking ASA or NSAIDs and patients witheither heartburn-dominant or -nondominant dyspepsia, rec-ommendations are provided on once-in-a-lifetimeendoscopy in patients with long-standing dyspepsia, the agecut-off above which initial investigation is recommended,and the need for the treatment of H pylori infection inpatients receiving long-term acid suppressive therapy.Recent clinical data, including primary care-based studiesfrom Canada, have provided grade A, level 1 evidence formany of the treatment recommendations. Future studiesshould help to optimize the management of dyspepsia in primarycare.

ACKNOWLEDGEMENTS: The following people weremembers of the CanDys Working Group and contributed to thiswork: Dr William Bartle, University of Toronto, PharmacyDepartment, Sunnybrook Health Sciences Centre, Toronto,Ontario; Dr Patricia Blackshaw, Surrey Memorial Hospital,Surrey, British Columbia; Dr Brian Craig, Department of FamilyMedicine, Dalhousie University, Department of FamilyMedicine, Atlantic Health Sciences Corporation, Saint JohnRegional Hospital Facility, Saint John, New Brunswick;Dr Krishnasamy Govender, Department of General Practice,Regina Health District, Regina, Saskatchewan; Dr BernardMarlow, Department of Family and Community Medicine,University of Toronto, Toronto, Ontario; Dr RichardMcCammon, Physician Manager (retired), Salvation Army GraceGeneral Hospital, Winnipeg, Manitoba; and Dr RobertWoodland, Department of Family Practice, Health CareCorporation, St John’s, Newfoundland.






REFERENCES

1. Veldhuyzen van Zanten SJ, Flook N, Chiba N, et al. An evidence-

based approach to the management of uninvestigated dyspepsia in

the era of Helicobacter pylori. Canadian Dyspepsia Working Group.

CMAJ 2000;162(Suppl 12):S3-23.

2. Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR,

Tytgat GN. Functional gastroduodenal disorders. Gut

1999;45(Suppl 2):II37-42.

3. Chiba N, Van Zanten SJ, Sinclair P, Ferguson RA, Escobedo S,

Grace E. Treating Helicobacter pylori infection in primary care

patients with uninvestigated dyspepsia: The Canadian adult

dyspepsia empiric treatment-Helicobacter pylori positive (CADET-

Hp) randomised controlled trial. BMJ 2002;324:1012-6.

4. Moayyedi P, Feltbower R, Brown J, et al. Effect of population

screening and treatment for Helicobacter pylori on dyspepsia and

quality of life in the community: A randomised controlled trial.

Leeds HELP Study Group. Lancet 2000;355:1665-9.

5. Wildner-Christensen M, Moller Hansen J, Schaffalitzky De

Muckadell OB. Rates of dyspepsia one year after Helicobacter pyloriscreening and eradication in a Danish population. Gastroenterology

2003;125:372-9.

6. Thomson AB, Barkun AN, Armstrong D, et al. The prevalence of

clinically significant endoscopic findings in primary care patients

with uninvestigated dyspepsia: The Canadian Adult Dyspepsia

Empiric Treatment – Prompt Endoscopy (CADET-PE) study.

Aliment Pharmacol Ther 2003;17:1481-91. (Erratum in 2004;20:72).

7. Talley NJ, Weaver AL, Tesmer DL, Zinsmeister AR. Lack of

discriminant value of dyspepsia subgroups in patients referred for

upper endoscopy. Gastroenterology 1993;105:1378-86.

8. Barkun A, Bardou M, Marshall JK. Nonvariceal Upper GI Bleeding

Consensus Conference Group. Consensus recommendations for

managing patients with nonvariceal upper gastrointestinal bleeding.

Ann Intern Med 2003;139:843-57.

9. The Society for Surgery of the Alimentary Tract (SSAT), American

Gastroenterological Association (AGA), American Society for

Gastrointestinal Endoscopy (ASGE) Consensus Panel. Management

of Barrett’s esophagus. J Gastrointest Surg 2000;4:115-6.

10. Sampliner RE. The Practice Parameters Committee of the American

College of Gastroenterology. Updated guidelines for the diagnosis,

surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol

2002;97:1888-95.

11. Axon AT, Bell GD, Jones RH, Quine MA, McCloy RF. Guidelines

on appropriate indications for upper gastrointestinal endoscopy.

Working Party of the Joint Committee of the Royal College of

Physicians of London, Royal College of Surgeons of England, Royal

College of Anaesthetists, Association of Surgeons, the British

Society of Gastroenterology, and the Thoracic Society of Great

Britain. BMJ 1995;310:853-6.

12. de Wit NJ, Mendive J, Seifert B, Cardin F, Rubin G. Guidelines on

the management of H pylori in primary care: Development of an

implementation strategy. Fam Pract 2000;17(Suppl 2):S27-32.

13. Talley NJ, Axon A, Bytzer P, Holtmann G, Lam SK, van Zanten S.

Management of uninvestigated and functional dyspepsia: A Working

Party report for the World Congresses of Gastroenterology 1998.

Aliment Pharmacol Ther 1999;13:1135-48.

14. The British Society of Gastroenterology guidelines on dyspepsia.

London: British Society of Gastroenterology, 2002.

<www.bsg.org.uk/pdf_word_docs/dyspepsia.doc> (Version current at

February 15, 2005).

15. The Scottish Intercollegiate Guidelines Network (SIGN). Dyspepsia.

Edinburgh: Scottish Intercollegiate Guidelines Network, 2003.

<http://www.sign.ac.uk/guidelines/fulltext/68/index.html> (Version

current at February 15, 2005).

16. Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick AM,

Vakil N. Screening and surveillance for Barrett esophagus in high-

risk groups: A cost-utility analysis. Ann Intern Med 2003;138:176-86.

17. Canga C III, Vakil N. Upper GI malignancy, uncomplicated

dyspepsia, and the age threshold for early endoscopy. Am J

Gastroenterol 2002;97:600-3.

18. Breslin NP, Thomson AB, Bailey RJ, et al. Gastric cancer and other

endoscopic diagnoses in patients with benign dyspepsia. Gut

2000;46:93-7.

19. Voutilainen M, Mantynen T, Kunnamo I, Juhola M, Mecklin JP,

Farkkila M. Impact of clinical symptoms and referral volume on

endoscopy for detecting peptic ulcer and gastric neoplasms. Scand J


20. Meineche-Schmidt V, Jorgensen T. Alarm symptoms in patients with

dyspepsia: A three-year prospective study from general practice.

Scand J Gastroenterol 2002;37:999-1007.

21. Manes G, Balzano A, Marone P, Lioniello M, Mosca S.

Appropriateness and diagnostic yield of upper gastrointestinal

endoscopy in an open-access endoscopy system: A prospective

observational study based on the Maastricht guidelines. Aliment

Pharmacol Ther 2002;16:105-10.

22. Falk GW. Barrett’s esophagus. Gastroenterology 2002;122:1569-91.

23. Avidan B, Sonnenberg A, Schnell TG, Sontag SJ. There are no

reliable symptoms for erosive oesphagitis and Barrett’s oesophagus:

Endoscopic diagnosis is still essential. Aliment Pharmacol Ther

2002;16:735-42.

24. Avidan B, Sonnenberg A, Schnell TG, Sontag SJ. Hiatal hernia and

acid reflux frequency predict presence and length of Barrett’s

esophagus. Dig Dis Sci 2002;47:256-64.

25. Eckardt VF, Kanzler G, Bernhard G. Life expectancy and cancer risk

in patients with Barrett’s esophagus: A prospective controlled

investigation. Am J Med 2001;111:33-7.

26. Katzka DA, Rustgi AK. Gastroesophageal reflux disease and Barrett’s

esophagus. Med Clin North Am 2000;84:1137-61.

27. National Cancer Institute of Canada. Canadian Cancer Statistics.

Toronto: National Cancer Institute of Canada, 2002.

28. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic

gastroesophageal reflux as a risk factor for esophageal

adenocarcinoma. N Engl J Med 1999;340:825-31.

29. Shaheen N, Ransohoff DF. Gastroesophageal reflux, Barrett’s

esophagus and esophageal cancer: Scientific review. JAMA

2002;287:1972-81.

30. Avidan B, Sonnenberg A, Schnell TG, Chejfec G, Metz A,

Sontag SJ. Hiatal hernia size, Barrett’s length, and severity of acid

reflux are all risk factors for esophageal adenocarcinoma. Am J


31. Peterson WL, American Gastroenterological Association Consensus

Development Panel. Improving the management of GERD: Evidence-

based therapeutic strategies. Richmond: AGA Press 2002:1-21.

32. Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical

management of Barrett’s esophagus with high-grade dysplasia.

Gastroenterology 2001;120:1607-19.

33. Spechler SJ. Clinical practice. Barrett’s Esophagus. N Engl J Med

2002;346:836-42.

34. Fass R, Hell RW, Garewal HS, et al. Correlation of oesophageal acid

exposure with Barrett’s oesophagus length. Gut 2001;48:310-3.

35. Fass R, Ofman JJ. Gastroesophageal reflux disease – should we adopt

a new conceptual framework? Am J Gastroenterol 2002;97:1901-9.

36. Csendes A, Burdiles P, Braghetto I, et al. Dysplasia and

adenocarcinoma after classic antireflux surgery in patients with

Barrett’s esophagus: The need for long-term subjective and objective

follow-up. Ann Surg 2002;235:178-85.

37. Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical

and surgical therapies for gastroesophageal reflux disease: Follow-up

of a randomized controlled trial. JAMA 2001;285:2331-8.

38. Fennerty MB, Triadafilopoulos G. Barrett’s-related esophageal

adenocarcinoma: Is chemoprevention a potential option? Am J


39. Armstrong D. Motion – all patients with GERD should be offered

once in a lifetime endoscopy: Arguments for the motion. Can J


40. Sonnenberg A, Soni A, Sampliner RE. Medical decision analysis of

endoscopic surveillance of Barrett’s oesophagus to prevent

oesophageal adenocarcinoma. Aliment Pharmacol Ther

2002;16:41-50.

41. Gudlaugsdottir S, van Blankenstein M, Dees J, Wilson JH. A

majority of patients with Barrett’s oesophagus are unlikely to benefit

from endoscopic cancer surveillance. Eur J Gastroenterol Hepatol

2001;13:639-45.

42. Chiba N. Motion – screening and surveillance of Barrett’s epithelium


is practical and cost effective: Arguments against the motion. Can J


43. Dent J, Brun J, Fendrick AM, et al. An evidence-based appraisal of

reflux disease management – the Genval Workshop Report. Gut

1999;44(Suppl 2):S1-16.

44. Streitz JM Jr, Andrews CW Jr, Ellis FH Jr. Endoscopic surveillance of

Barrett’s esophagus. Does it help? J Thorac Cardiovasc Surg

1993;105:383-7.

45. van Sandick JW, van Lanschot JJ, Tytgat GN, Offerhaus GJ,

Obertop H. Barrett oesophagus and adenocarcinoma: An overview of

epidemiologic, conceptual and clinical issues. Scand J Gastroenterol

2001;234(Suppl):51-60.

46. Peters JH. The management of dysplastic Barrett’s esophagus: Where

do we go from here? Ann Surg Oncol 2002;9:215-6.

47. Macdonald CE, Wicks AC, Playford RJ. Final results from 10-year

cohort of patients undergoing surveillance for Barrett’s oesophagus:

Observational study. BMJ 2000;321:1252-5.

48. Nietert PJ, Silverstein MD, Mokhashi MS, et al. Cost-effectiveness

of screening a population with chronic gastroesophageal reflux.

Gastrointest Endosc 2003;57:311-8.

49. Castell DO. Medical, surgical, and endoscopic treatment of

gastroesophageal reflux disease and Barrett’s esophagus. J Clin


50. Peters FT, Ganesh S, Kuipers EJ, et al. Endoscopic regression of

Barrett’s oesophagus during omeprazole treatment; a randomised

double blind study. Gut 1999;45:489-94. (Erratum in 2000;47:154-5).

51. Corey KE, Schmitz BA, Shaheen NJ. Does surgical antireflux

procedure decrease the incidence of esophageal adenocarcinoma in

Barret’s esophagus? A meta-analysis. Am J Gastroenterol

2003;98:2390-4.

52. Stichtenoth DO, Frolich JC. The second generation of COX-2

inhibitors: What advantages do the newest offer? Drugs 2003;63:33-45.

53. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity

with celecoxib vs nonsteroidal anti-inflammatory drugs for

osteoarthritis and rheumatoid arthritis: The CLASS study: A

randomized controlled trial. Celecoxib Long-term Arthritis Safety

Study. JAMA 2000;284:1247-55.

54. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper

gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA

1999;282:1929-33.

55. MacDonald TM, Morant SV, Robinson GC, et al. Association of

upper gastrointestinal toxicity of non-steroidal anti-inflammatory

drugs with continued exposure: Cohort study. BMJ 1997;315:1333-7.

56. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding

and perforation associated with individual non-steroidal anti-

inflammatory drugs. Lancet 1994;343:769-72. Erratum in: Lancet

1994;343:1048.

57. Ofman JJ, Maclean CH, Straus WL, et al. Meta-analysis of dyspepsia

and nonsteroidal antiinflammatory drugs. Arthritis Rheum

2003;49:508-18.

58. Laheij RJ, Jansen JB, Verbeek AL, Verheugt FW. Helicobacter pyloriinfection as a risk factor for gastrointestinal symptoms in patients

using aspirin to prevent ischaemic heart disease. Aliment Pharmacol

Ther 2001;15:1055-9.

59. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long

term use of aspirin: Meta-analysis. BMJ 2000;321:1183-7.

60. Straus WL, Ofman JJ, MacLean C, et al. Do NSAIDs cause

dyspepsia? A meta-analysis evaluating alternative dyspepsia

definitions. Am J Gastroenterol 2002;97:1951-8.

61. Bannwarth B, Treves R, Euller-Ziegler L, Rolland D, Ravaud P,

Dougados M. Adverse events associated with rofecoxib therapy:

Results of a large study in community-derived osteoarthritic patients.

Drug Saf 2003;26:49-54.

62. Goldstein JL, Kivitz AJ, Verburg KM, Recker DP, Palmer RC,

Kent JD. A comparison of the upper gastrointestinal mucosal effects

of valdecoxib, naproxen and placebo in healthy elderly subjects.


63. Wolfe F, Anderson J, Burke TA, Arguelles LM, Pettitt D.

Gastroprotective therapy and risk of gastrointestinal ulcers: Risk

reduction by COX-2 therapy. J Rheumatol 2002;29:467-73.

64. Makarowski W, Zhao WW, Bevirt T, Recker DP. Efficacy and safety

of the COX-2 specific inhibitor valdecoxib in the management of

osteoarthritis of the hip: A randomized, double-blind, placebo-

controlled comparison with naproxen. Osteoarthritis Cartilage

2002;10:290-6.

65. Sikes DH, Agrawal NM, Zhao WW, Kent JD, Recker DP,

Verburg KM. Incidence of gastroduodenal ulcers associated with

valdecoxib compared with that of ibuprofen and diclofenac in

patients with osteoarthritis. Eur J Gastroenterol Hepatol

2002;14:1101-11.

66. Hunt RH, Harper S, Watson DJ, et al. The gastrointestinal safety of

the COX-2 selective inhibitor etoricoxib assessed by both endoscopy

and analysis of upper gastrointestinal events. Am J Gastroenterol

2003;98:1725-33.

67. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase

inhibitors and the antiplatelet effects of aspirin. N Engl J Med

2001;345:1809-17.

68. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection

and non-steroidal anti-inflammatory drugs in peptic-ulcer disease:

A meta-analysis. Lancet 2002;359:14-22.

69. Lai KC, Lau CS, Ip WY, et al. Effect of treatment of Helicobacterpylori on the prevention of gastroduodenal ulcers in patients

receiving long-term NSAIDs: A double-blind, placebo-controlled

trial. Aliment Pharmacol Ther 2003;17:799-805.

70. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl

J Med 2002;347:2162-4.

71. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of

recurrences of ulcer complications from long-term low-dose aspirin

use. N Engl J Med 2002;346:2033-8.

72. Holvoet J, Terriere L, Van Hee W, Verbist L, Fierens E,

Hautekeete ML. Relation of upper gastrointestinal bleeding to non-

steroidal anti-inflammatory drugs and aspirin: A case-control study.

Gut 1991;32:730-4.

73. Clinch D, Banerjee AK, Ostick G. Absence of abdominal pain in

elderly patients with peptic ulcer. Age Ageing 1984;13:120-3.

74. Mellem H, Stave R, Myren J, et al. Symptoms in patients with peptic

ulcer and hematemesis and/or melena related to the use of non-

steroid anti-inflammatory drugs. Scand J Gastroenterol

1985;20:1246-8.

75. Matthewson K, Pugh S, Northfield TC. Which peptic ulcer patients

bleed? Gut 1988;29:70-4.

76. Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of

NSAID-related upper gastrointestinal clinical events: Results of a

double-blind outcomes study in patients with rheumatoid arthritis.


77. Chalmers TC, Berrier J, Hewitt P, et al. Meta-analysis of randomized

controlled trials as a method of estimating rare complications of non-

steroidal anti-inflammatory drug therapy. Aliment Pharmacol Ther

1988;2(Suppl 1):9-26.

78. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious

gastrointestinal complications related to use of nonsteroidal anti-

inflammatory drugs. A meta-analysis. Ann Intern Med

1991;115:787-96.

79. van Pinxteren B, Numans ME, Lau J, de Wit NJ, Hungin AP,

Bonis PA. Short-term treatment of gastroesophageal reflux disease.

J Gen Intern Med 2003;18:755-63.

80. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing

and symptom relief in grade II to IV gastroesophageal reflux disease:

A meta-analysis. Gastroenterology 1997;112:1798-810.

81. Vigneri S, Termini R, Leandro G, et al. A comparison of five

maintenance therapies for reflux esophagitis. N Engl J Med

1995;333:1106-10.

82. Galmiche JP, Barthelemy P, Hamelin B. Treating the symptoms of

gastro-oesophageal reflux disease: A double-blind comparison of

omeprazole and cisapride. Aliment Pharmacol Ther

1997;11:765-73.

83. Armstrong D, Barkun AN, Chiba N, et al, and CADET HR

Investigators. Initial PPI therapy is most effective in the

management of heartburn-dominant uninvestigated dyspepsia (UD)

in primary care practice (PCP) – The CADET-HR study. Can J

Gastroenterol 2002;16(Suppl A):97A. (Abst)

84. Venables TL, Newland RD, Patel AC, Hole J, Wilcock C,Turbitt ML.

Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once

daily, or ranitidine 150 milligrams twice daily, evaluated as initial




therapy for the relief of symptoms of gastro-oesophageal reflux

disease in general practice. Scand J Gastroenterol 1997;32:965-73.

85. Carlsson R, Dent J, Watts R, et al. Gastro-oesophageal reflux disease

in primary care: An international study of different treatment

strategies with omeprazole. International GORD Study Group. Eur J

Gastroenterol Hepatol 1998;10:119-24.

86. Lind T, Havelund T, Carlsson R, et al. Heartburn without

oesophagitis: Efficacy of omeprazole therapy and features determining

therapeutic response. Scand J Gastroenterol 1997;32:974-9.

87. Vakil N, Fennerty MB. Direct comparative trials of the efficacy of

proton pump inhibitors in the management of gastro-oesophageal

reflux disease and peptic ulcer disease. Aliment Pharmacol Ther

2003;18:559-68.

88. Edwards SJ, Lind T, Lundell L. Systematic review of proton pump

inhibitors for the acute treatment of reflux oesophagitis. Aliment


89. Klok RM, Postma MJ, van Hout BA, Brouwers JR. Meta-analysis:

Comparing the efficacy of proton pump inhibitors in short-term use.


90. Armstrong D, Veldhuyzen van Zanten SJO, Barkun AN, et al, and

the CAST Study Investigators. Symptom response at one week to

predict outcome at four weeks with esomeprazole (E) in heartburn-

dominant uninvestigated dyspepsia (HBDUD) patients: The

confirmatory acid suppression (CAST) test. Can J Gastroenterol

2003;17(Suppl A):A85. (Abst)

91. van Bommel MJ, Numans ME, de Wit NJ, Stalman WA.

Consultations and referrals for dyspepsia in general practice – a one

year database survey. Postgrad Med J 2001;77:514-8.

92. Majumdar SR, Soumerai SB, Francis FA, et al. Chronic acid-related

disorders are common and underinvestigated. Am J Gastroenterol

2003;98:2409-14.

93. Jacobson BC, Ferris TG, Shea TL, Mahlis EM, Lee TH, Wang TC.

Who is using chronic acid suppression therapy and why? Am J


94. Hansen JM, Bytzer P, Bondesen S, Schaffalitzky de Muckadell OB.

Efficacy and outcome of an open access endoscopy service. Dan Med

Bull 1991;38:288-90.

95. Quadri A, Vakil N. Health-related anxiety and the effect of open-

access endoscopy in US patients with dyspepsia. Aliment Pharmacol

Ther 2003;17:835-40.

96. Fennerty MB. The continuum of GERD complications. Cleve Clin J

Med 2003;70(Suppl 5):S33-50.

97. Locke GR III. Natural history of nonerosive reflux disease. Is all

gastroesophageal reflux disease the same? What is the evidence?

Gastroenterol Clin North Am 2002;31(Suppl 4):S59-66.

98. Talley NJ. Natural history of reflux esophagitis: What is the risk of

progression and does it matter clinically? Gastroenterol Hepatol

2002;17:1247-9.

99. Manabe N, Yoshihara M, Sasaki A, Tanaka S, Haruma K,

Chayama K. Clinical characteristics and natural history of patients

with low-grade reflux esophagitis. J Gastroenterol Hepatol

2002;17:949-54.

100. Klinkenberg-Knol EC, Festen HP, Meuwissen SG. Pharmacological

management of gastro-oesophageal reflux disease. Drugs

1995;49:695-710.

101. Dent J, Talley NJ. Overview: Initial and long-term management of

gastro-oesophageal reflux disease. Aliment Pharmacol Ther

2003;17(Suppl 1):53-7.

102. Maton PN. Profile and assessment of GERD pharmacotherapy. Cleve

Clin J Med 2003;70(Suppl 5):S51-70.

103. Tutuian R, Castell DO. Management of gastroesophageal reflux

disease. Am J Med Sci 2003;326:309-18.

104. Lamberts R, Brunner G, Solcia E. Effects of very long (up to 10

years) proton pump blockade on human gastric mucosa. Digestion

2001;64:205-13.

105. Howden CW. Potent versus mild acid suppression in peptic ulcer

disease. Hepatogastroenterology 1992;39(Suppl 1):45-6.

106. Freston JW. Long-term acid control and proton pump inhibitors:

Interactions and safety issues in perspective. Am J Gastroenterol

1997;92(Suppl 4):51S-7S.

107. Howden CW, Henning JM, Huang B, Lukasik N, Freston JW.

Management of heartburn in a large, randomized, community-based

study: Comparison of four therapeutic strategies. Am J Gastroenterol

2001;96:1704-10. (Erratum in 2001;96:2809).

108. Inadomi JM, Jamal R, Murata GH, et al. Step-down management of

gastroesophageal reflux disease. Gastroenterology

2001;121:1095-100.

109. Bardhan KD, Muller-Lissner S, Bigard MA, et al. Symptomatic

gastro-oesophageal reflux disease: Double blind controlled study of

intermittent treatment with omeprazole or ranitidine. The European

Study Group. BMJ 1999;318:502-7.

110. Quartero AO, Numans ME, Post MW, de Melker RA, de Wit NJ.

One-year prognosis of primary care dyspepsia: Predictive value of

symptom pattern, Helicobacter pylori and GP management. Eur J


111. Lind T, Havelund T, Lundell L, et al. On demand therapy with

omeprazole for the long-term management of patients with heartburn

without oesophagitis – a placebo-controlled randomized trial.


112. Talley NJ, Venables TL, Green JR, et al. Esomeprazole 40 mg and

20 mg is efficacious in the long-term management of patients with

endoscopy-negative gastro-oesophageal reflux disease: A placebo-

controlled trial of on-demand therapy for 6 months. Eur J


113. Wahlqvist P, Junghard O, Higgins A, Green J. Cost effectiveness of

proton pump inhibitors in gastro-oesophageal reflux disease without

oesophagitis: Comparison of on-demand esomeprazole with

conventional omeprazole strategies. Pharmacoeconomics

2002;20:267-77.

114. Bytzer P. On-demand therapy for gastro-oesophageal reflux disease.

Eur J Gastroenterol Hepatol 2001;13(Suppl 1):S19-22.

115. Porro GB, Pace F. Rationale and efficacy of medical therapy for

gastrooesophageal reflux disease. J Intern Med 1993;234:387-96.

116. Zacny J, Zamakhshary M, Veldhuyzen van Zanten S. A systematic

review of the efficacy of intermittent and on-demand therapy with

histamine H2-receptor antagonists or proton pump inhibitors for

GERD patients. Aliment Pharmacol Ther 2005 (In press)

117. Spechler SJ. Comparison of medical and surgical therapy for

complicated gastroesophageal reflux disease in veterans. The

Department of Veterans Affairs Gastroesophageal Reflux Study

Group. N Engl J Med 1992;326:786-92.

118. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysis

of factors predicting outcomes after laparoscopic Nissen

fundoplication. J Gastrointest Surg 1999;3:292-300.

119. McMahon RL, Mercer CD. National trends in gastroesophageal

reflux surgery. Can J Surg 2000;43:48-52.

120. Nilsson G, Larsson S, Johnsson F. Randomized clinical trial of

laparoscopic versus open fundoplication: Evaluation of psychological

well-being and changes in everyday life from a patient perspective.

Scand J Gastroenterol 2002;37:385-91.

121. Chrysos E, Tsiaoussis J, Athanasakis E, Zoras O, Vassilakis JS,

Xynos E. Laparoscopic vs open approach for Nissen fundoplication.

A comparative study. Surg Endosc 2002;16:1679-84.

122. Wenner J, Nilsson G, Oberg S, Melin T, Larsson S, Johnsson F.

Short-term outcome after laparoscopic and open 360 degrees

fundoplication. A prospective randomized trial. Surg Endosc

2001;15:1124-8.

123. Luostarinen M, Virtanen J, Koskinen M, Matikainen M, Isolauri J.

Dysphagia and oesophageal clearance after laparoscopic versus open

Nissen fundoplication. A randomized, prospective trial. Scand J


124. Nilsson G, Larsson S, Johnsson F. Randomized clinical trial of

laparoscopic versus open fundoplication: Blind evaluation of

recovery and discharge period. Br J Surg 2000;87:873-8.

125. Bais JE, Bartelsman JF, Bonjer HJ, et al. Laparoscopic or

conventional Nissen fundoplication for gastro-oesophageal reflux

disease: Randomised clinical trial. The Netherlands Antireflux

Surgery Study Group. Lancet 2000;355:170-4.

126. Heikkinen TJ, Haukipuro K, Bringman S, Ramel S, Sorasto A,

Hulkko A. Comparison of laparoscopic and open Nissen

fundoplication 2 years after operation. A prospective randomized

trial. Surg Endosc 2000;14:1019-23.

127. Lundell L, Miettinen P, Myrvold HE, et al. Continued (5-year)

follow-up of a randomized clinical study comparing antireflux surgery




and omeprazole in gastroesophageal reflux disease. J Am Coll Surg

2001;192:172-81.

128. Triadafilopoulos G, DiBaise JK, Nostrant TT, et al. The Stretta

procedure for the treatment of GERD: 6 and 12 month follow-up of

the US open label trial. Gastrointest Endosc 2002;55:149-56.

129. Johnson DA, Ganz R, Aisenberg J, et al. Endoscopic implantation of

enteryx for treatment of GERD: 12-month results of a prospective,

multicenter trial. Am J Gastroenterol 2003;98:1921-30.

130. Fennerty MB. Endoscopic suturing for treatment of GERD.

Gastrointest Endosc 2003;57:390-5.

131. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of

Helicobacter pylori in patients with gastro-oesophageal reflux disease:

Systematic review. BMJ 2003;326:737.

132. Sharma P, Vakil N. Review article: Helicobacter pylori and reflux

disease. Aliment Pharmacol Ther 2003;17:297-305.

133. Vigneri S, Termini R, Savarino V, Pace F. Review article: Is

Helicobacter pylori status relevant in the management of GORD?

Aliment Pharmacol Ther 2000;14(Suppl 3):31-42.

134. Malfertheiner P, Gerards C. Helicobacter pylori infection and gastro-

oesophageal reflux disease: Coincidence or association? Baillieres

Best Pract Res Clin Gastroenterol 2000;14:731-41.

135. Labenz J, Blum AL, Bayerdorffer E, Meining A, Stolte M, Borsch G.

Curing Helicobacter pylori infection in patients with duodenal ulcer

may provoke reflux esophagitis. Gastroenterology

1997;112:1442-7.

136. Morini S, Zullo A, Hassan C, Lorenzetti R, Stella F, Martini MT.

Gastric cardia inflammation: Role of Helicobacter pylori infection and

symptoms of gastroesophageal reflux disease. Am J Gastroenterol

2001;96:2337-40.

137. Schwizer W, Thumshim M, Dent J, et al. Helicobacter pylori and

symptomatic relapse of gastro-oesophageal reflux disease:

A randomized controlled trial. Lancet 2001;357:1738-42.

138. Verma S, Giaffer MH. Helicobacter pylori eradication ameliorates

symptoms and improves quality of life in patients on long-term acid

suppression. A large prospective study in primary care. Dig Dis Sci

2002;47:1567-74.

139. Moayyedi P, Bardhan C, Young L, Dixon MF, Brown L, Axon AT.

Helicobacter pylori eradication does not exacerbate reflux symptoms in

gastroesophageal reflux disease. Gastroenterology 2001;121:1120-6.

140. Cremonini F, Di Caro S, Delgado-Aros S, et al. Meta-analysis: The

relationship between Helicobacter pylori infection and gastro-

oesophageal reflux disease. Aliment Pharmacol Ther

2003;18:279-89.

141. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis

and Helicobacter pylori infection in patients with reflux esophagitis

treated with omeprazole or fundoplication. N Engl J Med

1996;334:1018-22.

142. Yamada T, Miwa H, Fujino T, Hirai S, Yokoyama T, Sato N.

Improvement of gastric atrophy after Helicobacter pylori eradication

therapy. J Clin Gastroenterol 2003;36:405-10.

143. Ohkusa T, Fujiki K, Takashimizu I, et al. Improvement in atrophic

gastritis and intestinal metaplasia in patients in whom Helicobacterpylori was eradicated. Ann Intern Med 2001;134:380-6.

144. Satoh K. Does eradication of Helicobacter pylori reverse atrophic

gastritis or intestinal metaplasia? Data from Japan. Gastroenterol

Clin North Am 2000;29:829-35.

145. Ohkuma K, Okada M, Murayama H, et al. Association of

Helicobacter pylori infection with atrophic gastritis and intestinal

metaplasia. J Gastroenterol Hepatol 2000;15:1105-12.

146. Kim N, Lim SH, Lee KH, Choi SE. Long-term effect of Helicobacterpylori eradication on gastric metaplasia in patients with duodenal

ulcer. J Clin Gastroenterol 1998;27:246-52.

147. DeLuca VA Jr, West AB, Haque S, et al. Long-term symptom

patterns, endoscopic findings, and gastric histology in Helicobacterpylori-infected and -uninfected patients. J Clin Gastroenterol

1998;26:106-12.

148. Zhou L, Sung JJ, Lin S, et al. A five-year follow-up study on the

pathological changes of gastric mucosa after H pylori eradication.

Chin Med J (Engl) 2003;116:11-4.

149. Satoh K, Kimura K, Takimoto T, Kihira K. A follow-up study of

atrophic gastritis and intestinal metaplasia after eradication of

Helicobacter pylori. Helicobacter 1998;3:236-40.

150. Moayyedi P, Feltbower R, Brown J, et al. Effect of population

screening and treatment for Helicobacter pylori on dyspepsia and

quality of life in the community: A randomised controlled trial.

Leeds HELP Study Group. Lancet 2000;355:1665-9.

151. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylorifor non-ulcer dyspepsia. Cochrane Database Syst Rev

2001;(1):CD002096. (Update in: Cochrane Database Syst Rev

2003;(1):CD002096).

152. Wildner-Christensen M, Moller Hansen J, Schaffalitzky De

Muckadell OB. Rates of dyspepsia one year after Helicobacter pyloriscreening and eradication in a Danish population. Gastroenterology

2003;125:372-9.

153. Manes G, Menchise A, de Nucci C, Balzano A. Empirical

prescribing for dyspepsia: Randomised controlled trial of test and

treat versus omeprazole treatment. BMJ 2003;326:1118.

154. Graham DY. Can therapy even be denied for Helicobacter pyloriinfection? Gastroenterology 1997;113(Suppl 6):S113-7.

155. Kuipers EJ, Thijs JC, Festen HP. The prevalence of Helicobacter pyloriin peptic ulcer disease. Aliment Pharmacol Ther

1995;9(Suppl 2):59-69.

156. Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spenard J.

Bismuth-based quadruple therapy using a single capsule of bismuth

biskalcitrate, metronidazole, and tetracycline given with omeprazole

versus omeprazole, amoxicillin, and clarithromycin for eradication of

Helicobacter pylori in duodenal ulcer patients: A prospective,

randomized, multicenter, North American trial. Am J Gastroenterol

2003;98:562-7.

157. Bardhan K, Bayerdorffer E, Veldhuyzen Van Zanten SJ, et al. The

HOMER Study: The effect of increasing the dose of metronidazole

when given with omeprazole and amoxicillin to cure Helicobacterpylori infection. Helicobacter 2000;5:196-201.

158. Veldhuyzen van Zanten S, Hunt RH, Cockeram A, et al. Adding

once-daily omeprazole 20 mg to metronidazole/amoxicillin treatment

for Helicobacter pylori gastritis: A randomized, double-blind trial

showing the importance of metronidazole resistance. Am J


159. Best LM, Haldane DJM, Veldhuyzen van Zanten SJO. Susceptibility

of Canadian Strains of Helicobacter pylori to metronidazole and

clarithromycin using four assay methods. Can J Gastroenterol

1998;12(Suppl A):106A(S92).

160. Fallone CA. Epidemiology of the antibiotic resistance of Helicobacterpylori in Canada. Can J Gastroenterol 2000;14:879-82.

161. Gisbert JP, Gonzalez L, Calvet X, et al. Proton pump inhibitor,

clarithromycin and either amoxycillin or nitroimidazole: A meta-

analysis of eradication of Helicobacter pylori. Aliment Pharmacol

Ther 2000;14:1319-28.

162. Laheij RJF, Rossum LG, Jansen JB, Straatman H,

Verbeek AL. Evaluation of treatment regimens to cure Helicobacterpylori infection – a meta-analysis. Aliment Pharmacol Ther

1999;13:857-64.

163. Fischbach LA, Goodman KJ, Feldman M, Aragaki C. Sources of

variation of Helicobacter pylori treatment success in adults worldwide:

A meta-analysis. Int J Epidemiol 2002;31:128-39.

164. Katelaris PH, Forbes GM, Talley NJ, Crotty B. A randomized

comparison of quadruple and triple therapies for Helicobacter pylorieradication: The QUADRATE Study. Gastroenterology

2002;123:1763-9.

165. Vergara M, Vallve M, Gisbert JP, Calvet X. Meta-analysis:

Comparative efficacy of different proton-pump inhibitors in triple

therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther

2003;18:647-54.

166. Hunt R, Thomson AB. Canadian Helicobacter pylori consensus

conference. Canadian Association of Gastroenterology. Can J


167. Graham DY, Hammoud F, El-Zimaity HM, Kim JG, Osato MS,

El-Serag HB. Meta-analysis: Proton pump inhibitor or H2-receptor

antagonist for Helicobacter pylori eradication. Aliment Pharmacol

Ther 2003;17:1229-36.

168. Gisbert JP, Pajares JM. Review article: Helicobacter pylori “rescue”

regimen when proton pump inhibitor-based triple therapies fail.


169. Graham DY, Opekun AR, Hammoud F, et al. Studies regarding the




mechanism of false negative urea breath tests with proton pump

inhibitors. Am J Gastroenterol 2003;98:1005-9.

170. Chiba N, Veldhuyzen Van Zanten SJ. 13C-Urea breath tests are the

noninvasive method of choice for Helicobacter pylori detection. Can J


171. Malfertheiner P, Megraud F, O’Morain C, et al; European HelicobacterPylori Study Group (EHPSG). Current concepts in the management

of Helicobacter pylori infection – the Maastricht 2-2000 Consensus

Report. Aliment Pharmacol Ther 2002;16:167-80.

172. Mirshahi F, Fowler G, Patel A, Shaw G. Omeprazole may exert both

a bacteriostatic and a bacteriocidal effect on the growth of

Helicobacter pylori (NCTC 11637) in vitro by inhibiting bacterial

urease activity. J Clin Pathol 1998;51:220-4.

173. Nakao M, Malfertheiner P. Growth inhibitory and bactericidal

activities of lansoprazole compared with those of omeprazole and

pantoprazole against Helicobacter pylori. Helicobacter 1998;3:21-7.

174. Savarino V, Bisso G, Pivari M, et al. Effect of omeprazole and

ranitidine on the accuracy of 13C-urea breath test (UBT). Gut

1998;43:A51 (Abst)

175. Savarino V, Vigneri S, Celle G. The 13C urea breath test in the

diagnosis of Helicobacter pylori infection. Gut 1999;45(Suppl 1):I18-22.

176. Dulbecco P, Gambaro C, Bilardi C, et al. Impact of long-term

ranitidine and pantoprazole on accuracy of [13C] urea breath test.

Dig Dis Sci 2003;48:315-21.

177. Chey WD, Spybrook M, Carpenter S, et al. Prolonged effect of

omeprazole on the 14C-urea breath test. Am J Gastroenterol

1996;91:89-92.

178. Katelaris PH, Connor SJ, Seow F, et al. The effect of short-term

omeprazole use on the accuracy of 13C-urea breath test in Helicobacterpylori infected patients. Gut 1998;43(Suppl 2):A53. (Abst)

179. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of

proton-pump inhibitor therapy on diagnostic testing of Helicobacterpylori. Ann Intern Med 1998;129:547-50.

180. El-Nujumi A, Hilditch TE, Williams C, McColl KE. Current or

recent proton pump inhibitor therapy markedly impairs the accuracy

of the [14C] urea breath test. Eur J Gastroenterol Hepatol

1998;10:759-64.

181. McColl KE, el-Nujumi A, Murray L, et al. The Helicobacter pyloribreath test: A surrogate marker for peptic ulcer disease in dyspeptic

patients. Gut 1997;40:302-6.

182. Chey WD, Woods M, Scheiman JM, Nostrant TT, DelValle J.

Lansoprazole and ranitidine affect the accuracy of the 14C-urea

breath test by a pH-dependent mechanism. Am J Gastroenterol

1997;92:446-50.

183. Cutler AF, Elnaggar M, Brooks E, O’Mara K. Effect of standard and

high dose ranitidine on [13C] urea breath test results. Am J


184. Savarino V, Tracci D, Dulbecco P, et al. Negative effect of ranitidine

on the results of urea breath test for the diagnosis of Helicobacterpylori. Am J Gastroenterol 2001;96:348-52.

185. Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D.

Pharmacological interventions for non-ulcer dyspepsia. Cochrane

Database Syst Rev 2000;(2):CD001960. (Update in: Cochrane

Database Syst Rev 2003;(1):CD001960).

186. Bolling-Sternevald E, Lauritsen K, Aalykke C, et al. Effect of

profound acid suppression in functional dyspepsia: A double-blind,

randomized, placebo-controlled trial. Scand J Gastroenterol

2002;37:1395-402.

187. Talley NJ, Meineche-Schmidt V, Pare P, et al. Efficacy of omeprazole

in functional dyspepsia: Double-blind, randomized, placebo-

controlled trials (the Bond and Opera studies). Aliment Pharmacol

Ther 1998;12:1055-65.

188. Veldhuyzen van Zanten S, Chiba N, Armstrong D, et al, and

CADET-HN Investigators. A double-blind randomised controlled

trial comparing omeprazole (Ome), ranitidine (Ran), cisapride (Cis)

and placebo (Pla) in 512 Helicobacter pylori (Hp) negative primary

care patients with uninvestigated dyspepsia (UD) – The CADET-

HN Study. Can J Gastroenterol 2002;16(Suppl A):5A. (Abst)

189. Delaney BC, Innes MA, Deeks J, et al. Initial management strategies

for dyspepsia. Cochrane Database Syst Rev 2001;(3):CD001961.

(Update in: Cochrane Database Syst Rev 2003;(2):CD001961).

190. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D.

Pharmacological interventions for non-ulcer dyspepsia. Cochrane

Database Syst Rev 2003;(1):CD001960. (Updated in: Database Syst

Rev 2003;(2):CD001961).

191. Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, Talley NJ.

Efficacy of cisapride and domperidone in functional (nonulcer)

dyspepsia: A meta-analysis. Am J Gastroenterol 2001;96:689-96.

192. Hatlebakk JG, Katz PO, Camacho-Lobato L, Castell DO. Proton

pump inhibitors: Better acid suppression when taken before a meal

than without a meal. Aliment Pharmacol Ther 2000;14:1267-72.

193. Katz PO, Hatlebakk JG, Castell DO. Gastric acidity and acid

breakthrough with twice-daily omeprazole or lansoprazole. Aliment


194. Hatlebakk JG, Katz PO, Kuo B, Castell DO. Nocturnal gastric

acidity and acid breakthrough on different regimens of omeprazole

40 mg daily. Aliment Pharmacol Ther 1998;12:1235-40.

195. Chiverton SG, Howden CW, Burget DW, Hunt RH. Omeprazole

(20 mg) daily given in the morning or evening: A comparison of

effects on gastric acidity, and plasma gastrin and omeprazole

concentration. Aliment Pharmacol Ther 1992;6:103-11.

196. Tougas G, Chen Y, Hwang P, Liu MM, Eggleston A. Prevalence and

impact of upper gastrointestinal symptoms in the Canadian

population: Findings from the DIGEST study. Domestic/International

Gastroenterology Surveillance Study. Am J Gastroenterol

1999;94:2845-54.

197. Maton PN, Burton ME. Antacids revisited. A review of their clinical

pharmacology and recommended therapeutic use. Drugs

1999;57:855-70.

198. Mullane J, Fung K, Starkey P, et al. A comparison of the effect of a

single dose of either calcium carbonate (1 g) or famotidine (10 mg)

on intragastric pH in normal healthy subjects. Gastroenterology

1997;112:A246. (Abst)

199. Collings KL, Rodriguez-Stanley S, Proskin HM, Robinson M,

Miner PB Jr. Clinical effectiveness of a new antacid chewing gum on

heartburn and oesophageal pH control. Aliment Pharmacol Ther

2002;16:2029-35.

200. Robinson M, Rodriguez-Stanley S, Miner PB, McGuire AJ,

Fung K, Ciociola AA. Effects of antacid formulation on postprandial

oesophageal acidity in patients with a history of episodic heartburn.


201. Reilly TG, Mann SG, Panos MZ, Walt RP. Low-dose famotidine and

cimetidine in single post-prandial doses: A placebo controlled

comparative study of overnight pH. Gut 1995;37:325-8.

202. Hamilton MI, Sercombe J, Pounder RE. Decrease of intragastric

acidity in healthy subjects dosed with ranitidine 75 mg, cimetidine

200 mg, or placebo. Dig Dis Sci 2002;47:54-7.

203. Sihvo S, Hemminki E. Self-medication of dyspepsia: How

appropriate is it? Scand J Gastroenterol 1997;32:855-61.

204. Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article:

Alginate-raft formulations in the treatment of heartburn and acid

reflux. Aliment Pharmacol Ther 2000;14:669-90.

205. Mann SG, Murakami A, McCarroll K, et al. Low dose famotidine in

the prevention of sleep disturbance caused by heartburn after an

evening meal. Aliment Pharmacol Ther 1995;9:395-401.

206. Paul K, Redman CM, Chen M. Effectiveness and safety of nizatidine,

75 mg, for the relief of episodic heartburn. Aliment Pharmacol Ther

2001;15:1571-7.

207. Feldman M. Comparison of the effects of over-the-counter

famotidine and calcium carbonate antacid on postprandial gastric

acid. A randomized controlled trial. JAMA 1996;275:1428-31.

208. Thompson Coon J, Ernst E. Systematic review: Herbal medicinal

products for non-ulcer dyspepsia. Aliment Pharmacol Ther

2002;16:1689-99.

209. Broussard CN, Richter JE. Treating gastro-oesophageal reflux disease

during pregnancy and lactation: What are the safest therapy options?

Drug Saf 1998;19:325-37.

210. Winbery SL, Blaho KE. Dyspepsia in pregnancy. Obstet Gynecol

Clin North Am 2001;28:333-50.

211. Adams S. Understanding indigestion and GORD. Prof Care Mother

Child 1999;9:143-6.

212. Alvarez-Sanchez A, Rey E, Achem SR, Diaz-Rubio M. Does

progesterone fluctuation across the menstrual cycle predispose to

gastroesophageal reflux? Am J Gastroenterol 1999;94:1468-71.




213. Dajani EZ. Gastroesophageal reflux disease: Pathophysiology and

pharmacology overview. J Assoc Acad Minor Phys 2000;11:7-11.

214. Nikfar S, Abdollahi M, Moretti ME, Magee LA, Koren G. Use of

proton pump inhibitors during pregnancy and rates of major

malformations: A meta-analysis. Dig Dis Sci 2002;47:1526-9.

215. Larson JD, Patatanian E, Miner PB Jr, Rayburn WF, Robinson MG.

Double-blind, placebo-controlled study of ranitidine for

gastroesophageal reflux symptoms during pregnancy. Obstet Gynecol

1997;90:83-7.

216. Williamson C. Drugs in pregnancy. Gastrointestinal disease. Best

Pract Res Clin Obstet Gynaecol 2001;15:937-52.

217. Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during

pregnancy for preventing hypertensive disorders and related

problems. Cochrane Database Syst Rev 2000;1:CD001059.

218. Candelli M, Carloni E, Armuzzi A, et al. Role of sucralfate in

gastrointestinal diseases. Panminerva Med 2000;42:55-9.

219. Henry A, Crowther C. Patterns of medication use during and prior

to pregnancy: The MAP study. Aust N Z J Obstet Gynaecol

2000;40:165-72.

220. Kennie N, Por CP, Evans MF. Does ranitidine work for gastroesophageal

symptoms during pregnancy? Can Fam Physician 1998;44:761-2.

221. Rayburn W, Liles E, Christensen H, Robinson M. Antacids vs

antacids plus non-prescription ranitidine for heartburn during

pregnancy. Int J Gynaecol Obstet 1999;66:35-7.

222. Ruigomez A, Garcia Rodriguez LA, Cattaruzzi C, et al. Use of

cimetidine, omeprazole, and ranitidine in pregnant women and

pregnancy outcomes. Am J Epidemiol 1999;150:476-81.

223. Lalkin A, Loebstein R, Addis A, et al. The safety of omeprazole

during pregnancy: A multicenter prospective controlled study. Am J

Obstet Gynecol 1998;179:727-30.

224. Gastro-oesophageal reflux during pregnancy: Treat with care. Drug

Ther Perspect 1999;13:7-11.

225. Marshall JK, Thompson AB, Armstrong D. Omeprazole for refractory

gastroesophageal reflux disease during pregnancy and lactation. Can

J Gastroenterol 1998;12:225-7.

226. Soo S, Moayyedi P, Deeks J, Delaney B, Lewis M, Forman D.

Psychological interventions for non-ulcer dyspepsia. Cochrane

Database Syst Rev 2001;(4):CD002301.

227. Lee S, Park M, Choi S, Nah Y, Abbey SE, Rodin G. Stress, coping, and

depression in non-ulcer dyspepsia patients. J Psychosom Res

2000;49:93-9.

228. Drossman DA. Importance of the psyche in heartburn and dyspepsia.

Aliment Pharmacol Ther 1997;11(Suppl 2):57-67.

229. Wiklund I, Butler-Wheelhouse P. Psychosocial factors and their role

in symptomatic gastroesophageal reflux disease and functional

dyspepsia. Scand J Gastroenterol Suppl 1996;220:94-100.

230. O’Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E,

Kroenke K. Antidepressant therapy for unexplained symptoms and

symptom syndromes. J Fam Pract 1999;48:980-90.

231. de Abajo FJ, Rodriguez LA, Montero D. Association between

selective serotonin reuptake inhibitors and upper gastrointestinal

bleeding: Population based case-control study. BMJ

1999;319:1106-9.

232. van Walraven C, Mamdani MM, Wells PS, Williams JI. Inhibition of

serotonin reuptake by antidepressants and upper gastrointestinal

bleeding in elderly patients: Retrospective cohort study. BMJ

2001;323:655-8.

233. Hamilton J, Guthrie E, Creed F, et al. A randomized controlled trial

of psychotherapy in patients with chronic functional dyspepsia.





Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

evidence-based recommendations for short- and long-term

Documents